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1.
J Biomed Nanotechnol ; 17(1): 78-89, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33653498

RESUMEN

Currently chemotherapy drugs are usually used as first-line treatments for castration-resistant prostate cancer (CRPC), but they are ineffective and accompanied by serious side effects. MicroRNA-34a (miR-34a) simultaneously targets multiple genes related to the cell apoptosis in CRPC cells without obvious side effects. It has shown great potential in the treatment of CRPC. Previous studies focused on miR-34a increasing the sensitivity of chemotherapy drugs to chemoresistant prostate cancer cells. There are few researches on miR-34a alone in the treatment of CRPC. But the macromolecular miR-34a is difficult to enter the cell and is easily degraded by nuclease. Therefore, we constructed methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) nanoparticles to encapsulate miR-34a (miR-34a/NP). The results showed that miR-34a/NP protects miR-34a from degradation by nucleases and can be phagocytized by PC-3 CRPC cells. Ultrasound induces microbubble cavitation (UIMC) improves cell membrane permeability and capillary gaps, and further promotes miR-34a/NP to enter cells PC-3 and prostate cancer xenografts. The miR-34a/NP that enters the cell and tumor tissue releases miR-34a, which suppressed CRPC cells PC-3 proliferation, promoted its apoptosis, and inhibited the growth of CRPC xenografts. Our research verified that miR-34a/NP, especially combined with UIMC, has a significant anti-tumor effect on CRPC.


Asunto(s)
MicroARNs , Nanopartículas , Neoplasias de la Próstata Resistentes a la Castración , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/genética , Microburbujas , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética
2.
Bull Cancer ; 108(4): 359-368, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33743960

RESUMEN

BACKGROUND: Overexpression of certain long non-coding RNAs (lncRNAs) promotes the progression of castration-resistant prostate cancer (CRPC). The significance and potential role of the lncRNA designated pituitary tumour-transforming 3, pseudogene (PTTG3P) in CRPC is unknown. METHODS: We detected PTTG3P expression by qPCR. Upregulated PTTG3P expression was performed to explore the role of PTTG3P in PCa cells resistant to ADT (androgen deprivation therapy). The relationship among PTTG3P, mir-146a-3p and PTTG1 were validated by qPCR, western blot and luciferase assay. RESULTS: PTTG3P levels were significantly increased in the androgen-independent PC cell lines, as well as in CRPC tissues compared with those of the androgen-dependent prostate cancer cell line LNCaP and tumour tissues of patients with hormone-naive prostate cancers. Enforced expression of PTTG3P in androgen-deprived LNCaP cells significantly enhanced survival, clonogenicity, and tumorigenicity. Further, PTTG3P acted as a competing endogenous RNA (ceRNA, natural miRNA sponge) to upregulate PTTG1 expression by competing for mir-146a-3p in the progression to CRPC. CONCLUSION: Our findings suggest that PTTG3P promotes the resistance of prostate cancer cells to androgen-deprivation therapy via upregulating PTTG1. PTTG3P may therefore represent a potential target for therapy of CRPC.


Asunto(s)
Adenocarcinoma/patología , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Largo no Codificante/genética , ARN Neoplásico/genética , Securina/biosíntesis , Securina/genética , Adenocarcinoma/genética , Antagonistas de Andrógenos/uso terapéutico , Anilidas/uso terapéutico , Animales , Antineoplásicos Hormonales/uso terapéutico , Unión Competitiva , Línea Celular Tumoral , Resistencia a Antineoplásicos , Xenoinjertos , Humanos , Masculino , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Trasplante de Neoplasias , Nitrilos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/genética , Seudogenes , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/metabolismo , Compuestos de Tosilo/uso terapéutico , Ensayo de Tumor de Célula Madre , Regulación hacia Arriba
3.
Nat Commun ; 12(1): 1714, 2021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33731701

RESUMEN

Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-ß induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.


Asunto(s)
Neoplasias Óseas/secundario , Carcinogénesis , Transición Epitelial-Mesenquimal , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Acetilación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencilaminas/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Ciclamas/uso terapéutico , Docetaxel/uso terapéutico , Humanos , Interleucina-11/genética , Interleucina-11/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Ratones , Mutación , Osteogénesis , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo
4.
Int J Nanomedicine ; 16: 315-327, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33469288

RESUMEN

Background: Castration-resistant prostate cancer (CRPC) is still considered incurable, even though the mechanisms of CRPC had been extensively researched. Studies have demonstrated that exosomes in the tumor microenvironment contribute to prostate cancer development and progression. However, the role of exosomes in the process of CRPC progression has not yet been determined. Methods: Co-culturing and exosome treatment assays combined with in vitro and in vivo assays were performed to determine the function of exosomes in the transformation of androgen-dependent prostate cancer (ADPC) cells into androgen-independent cells. Then, the mRNA expression profiles of ADPC cells and ADPC cells co-cultured with androgen-independent prostate cancer (AIPC) cell-derived exosomes were studied using microarrays. After silencing the expression of heme oxygenase-1 (HMOX1), Western blotting, quantitative real-time PCR, immunohistochemistry (IHC) studies, and MTS assay were used to confirm the mechanisms of exosome participation in CRPC progression. Results: The results showed that ADPC cells acquired tolerance for androgen deprivation due to the exosome-mediated communication between cells. AIPC cell-derived exosomes promoted the transformation of ADPC cells into androgen-independent cells in vivo and in vitro. Microarray analysis revealed that HMOX1 in ADPC cells was up-regulated after treatment with AIPC cell-derived exosomes. Further results showed that HMOX1 is overexpressed in human AIPC specimens and protects ADPC cells from androgen deprivation. Conclusions: Our findings revealed that exosomes contribute to CRPC progression via promoting the transition of prostate cancer cells into an androgen-independent growth stage by activating HMOX1.


Asunto(s)
Andrógenos/farmacología , Exosomas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Neoplasias de la Próstata/patología , Regulación hacia Arriba/efectos de los fármacos , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Exosomas/ultraestructura , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos NOD , Ratones SCID , Neoplasias de la Próstata/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Microambiente Tumoral
5.
J Med Chem ; 64(2): 909-924, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33470111

RESUMEN

Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Nitrilos/farmacología , Picolinas/farmacología , Piperidinas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Piridinas/farmacología , Compuestos de Espiro/farmacología , Antagonistas de Receptores Androgénicos/farmacocinética , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Biotransformación , Línea Celular Tumoral , Perros , Descubrimiento de Drogas , Resistencia a Antineoplásicos/genética , Hepatocitos/metabolismo , Humanos , Masculino , Modelos Moleculares , Mutación , Nitrilos/farmacocinética , Nitrilos/uso terapéutico , Picolinas/farmacocinética , Picolinas/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/uso terapéutico , Relación Estructura-Actividad
6.
Nat Commun ; 12(1): 401, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33452241

RESUMEN

Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.


Asunto(s)
Carcinogénesis/genética , Criptocromos/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata Resistentes a la Castración/genética , Reparación del ADN por Recombinación/genética , Anciano , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Andrógenos/metabolismo , Carcinogénesis/efectos de los fármacos , Línea Celular Tumoral , Secuenciación de Inmunoprecipitación de Cromatina , Criptocromos/genética , Roturas del ADN de Doble Cadena/efectos de los fármacos , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Estudios de Seguimiento , Puntos de Control de la Fase G2 del Ciclo Celular/genética , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Regiones Promotoras Genéticas/genética , Estudios Prospectivos , Próstata/patología , Próstata/cirugía , Prostatectomía , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia , RNA-Seq , Receptores Androgénicos/metabolismo , Reparación del ADN por Recombinación/efectos de los fármacos , Estudios Retrospectivos
7.
Bull Cancer ; 108(1): 55-66, 2021 Jan.
Artículo en Francés | MEDLINE | ID: mdl-33419531

RESUMEN

The editorial committee of the Bulletin du Cancer is proud to comply with his annual analysis of some of the worldwide updates in oncology that emerge in 2020. We know that all new breakthroughs will not be addressed and apologise for not being comprehensive, but we hope that the topics deciphered herein will bring the reader interesting information in his daily practice in gyneco-oncology, uro-oncology, neuro-oncology, digestive oncology, pneumo-oncology, hemato-oncology, pediatric oncology, or in palliative care.


Asunto(s)
Oncología Médica , Neoplasias/terapia , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Neoplasias del Sistema Digestivo/terapia , Femenino , Neoplasias de los Genitales Femeninos/terapia , Glioblastoma/terapia , Neoplasias Hematológicas/terapia , Humanos , Neoplasias Pulmonares/terapia , Masculino , Neoplasias Primarias Desconocidas/terapia , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/terapia , Neoplasias Urológicas/terapia
8.
J Urol ; 205(4): 977-986, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33332152

RESUMEN

PURPOSE: To characterize the global epidemiology of metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic castration-resistant prostate cancer (mCRPC). Additionally, to assess the prevalence of homologous recombination repair gene alterations (HRRm) and their prognostic impact in advanced disease setting. MATERIALS AND METHODS: A systematic literature review of real-world evidence published from January 2009 through May 2019 was conducted to assess global epidemiology and clinical practice trends for mCSPC, nmCRPC, mCRPC and HRRm; 4,732 papers were systematically screened for inclusion. Ten conference proceedings from 2014 through 2019 were reviewed. RESULTS: Of the screened articles 22 relevant publications were identified for this paper. Six publications reported global epidemiology of advanced prostate cancer. The prevalence of nmCRPC was estimated as 1.1% to 12.3% of prostate cancer cases and for mCRPC 1.2% to 2.1% of prostate cancer cases. No mCSPC prevalence was captured. Sixteen publications investigated HRRm prevalence in advanced prostate cancer with the majority conducted in mCRPC assessed using next-generation sequencing of tissue and germline samples. In mCRPC, the highest prevalence HRRm in both germline (3.3%-6.0%) and somatic (5.0%-15.1%) was BRCA2. Five publications reported the prognostic impact of HRRm in advanced prostate cancer. CONCLUSIONS: Published real-world evidence quantifying the prevalence of advanced prostate cancer and HRRm beyond mCRPC is sparse. Published data on HRRm, specifically BRCA2, are consistent with published clinical trial data for poly (ADP-ribose) polymerase inhibitors in mCRPC. In mCRPC, real-world evidence suggests that patients with HRRm have different clinical outcomes to noncarriers. More data are needed to better understand real-world patient segmentation and clinical outcomes for biomarkers given increasing interest in profiling.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Próstata Resistentes a la Castración/epidemiología , Neoplasias de la Próstata Resistentes a la Castración/genética , Reparación del ADN por Recombinación , ADN Tumoral Circulante/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Masculino , Metástasis de la Neoplasia , Prevalencia , Pronóstico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/patología
9.
Crit Rev Oncol Hematol ; 157: 103185, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33341506

RESUMEN

In last years several improvements have been made in the management of prostate cancer (PCa). Androgen receptor (AR) is considered the main driver in PCa growth and progression and most drugs are directed against AR pathway. Once PCa spreads outside the prostate, androgen deprivation therapy (ADT) represents the cornerstone of treatment in hormone-sensitive prostate cancer (HSPC). Unfortunately, the response is only transient and most patients eventually develop castration-resistant prostate cancer (CRPC). Most resistance mechanisms depend on maintenance of AR signalling in castration environment. Recent discoveries of multiple growth-promoting and survival pathways in PCa suggest the importance of alternative mechanisms involved in disease progression, such as DNA damage response pathway, PTEN/PI3K/AKT/mTOR pathway, cell cycle pathway, WNT pathway, TMPRSS2/ETS fusion, neuroendocrine pattern and immune system response. In this review, we discuss the interplay between AR signaling and other molecular pathways involved in PCa pathogenesis and their therapeutic implication in advanced disease.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Antagonistas de Andrógenos , Progresión de la Enfermedad , Humanos , Masculino , Fosfatidilinositol 3-Quinasas , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Receptores Androgénicos/genética
10.
Int J Mol Sci ; 21(24)2020 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-33339129

RESUMEN

Enzalutamide, an antiandrogen, is approved for therapy of castration resistant prostate cancer. Clinical applications have shown that approximately 30% of patients acquire resistance after a short period of treatment. However, the molecular mechanisms underlying this resistance is not completely understood. To identify transcriptomic signatures associated with acquisition of drug resistance we profiled gene expression of paired enzalutamide sensitive and resistant human prostate cancer LNCaP (lymph node carcinoma of the prostate) and C4-2B cells. Overlapping genes differentially regulated in the enzalutamide resistant cells were ranked by Ingenuity Pathway Analysis and their functional validation was performed using ingenuity knowledge database followed by confirmation to correlate transcript with protein expression. Analysis revealed that genes associated with cancer stem cells, such as POU5F1 (OCT4), SOX2, NANOG, BMI1, BMP2, CD44, SOX9, and ALDH1 were markedly upregulated in enzalutamide resistant cells. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with RUNX2, hedgehog, integrin signaling, and molecules associated with elastic fibers. Further examination of a patient cohort undergoing ADT and its comparison with no-ADT group demonstrated high expression of POU5F1 (OCT4), ALDH1, and SOX2 in ADT specimens, suggesting that they may be clinically relevant therapeutic targets. Altogether, our approach exhibits the potential of integrative transcriptomic analyses to identify critical genes and pathways of antiandrogen resistance as a promising approach for designing novel therapeutic strategies to circumvent drug resistance.


Asunto(s)
Andrógenos/deficiencia , Redes Reguladoras de Genes , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/genética , Transcriptoma , Antagonistas de Receptores Androgénicos/farmacología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Células Madre Neoplásicas/metabolismo , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología
11.
Int J Nanomedicine ; 15: 10305-10320, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33376323

RESUMEN

Purpose: The clinical management of patients with castration-resistant prostate cancer (CRPC) is difficult. However, novel treatment methods are gradually being introduced. Considering the adverse effects of traditional treatments, recent studies have investigated gene therapy as a method to combat CRPC; but, the application of long non-coding (lnc) RNA in gene therapy remains scarce, despite their promise. Therefore, it is imperative to develop a system that can efficiently deliver lncRNA for the treatment of CRPC. Here, we investigated the efficacy of a delivery system by introducing the plasmid-encoding tumor suppressor lncRNA MEG3 (pMEG3) in CRPC cells. Materials and Methods: An EpDT3 aptamer-linked poly(amidoamine) (PAMAM) dendrimer targeting EpCAM was used to deliver pMEG3 in CRPC cells. The PAMAM-PEG-EpDT3/pMEG3 nanoparticles (NPs) were tested using in vitro cellular assays including cellular uptake, entry, and CCK-8 measurement, and tumor growth inhibition, histological assessment, and safety evaluations in in vivo animal models. Results: The EpDT3 aptamer promoted endocytosis of PAMAM and PAMAM-PEG-EpDT3/pMEG3 NPs in CRPC cells. PAMAM-PEG-EpDT3/pMEG3 NPs exhibited a significant anti-CRPC effect, both in vivo and in vitro, when compared to that of unfunctionalized PAMAM-PEG/pMEG3 NPs. Conclusion: PAMAM-PEG-EpDT3/pMEG3 NPs can potentially improve gene therapy in CRPC cells.


Asunto(s)
Aptámeros de Nucleótidos/química , Dendrímeros/química , Terapia Genética/métodos , Plásmidos/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/terapia , ARN Largo no Codificante/genética , Animales , Línea Celular Tumoral , Portadores de Fármacos/química , Humanos , Masculino , Nanopartículas/química , Plásmidos/química , Polietilenglicoles/química
12.
Urol Clin North Am ; 47(4): 469-474, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33008497

RESUMEN

Multiple immunologic platforms have provided minimal impact in patients with metastatic castration-resistant prostate cancer, necessitating that novel approaches continue to be developed. Although checkpoint inhibitors have been largely ineffective, there remain small cohorts of patients who have durable responses but lack the conventional indicators for response to this class of drugs, that is, high mutational burden or significant genomic alterations, as seen in other solid tumors. This article presents an update on the evolution of immunotherapeutics that target a more lethal form of prostate cancer and provides the groundwork for future considerations as to how this field should proceed.


Asunto(s)
Quinasas Ciclina-Dependientes/genética , Regulación Neoplásica de la Expresión Génica , Inmunoterapia/métodos , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/terapia , Anciano , Productos Biológicos/uso terapéutico , Vacunas contra el Cáncer/administración & dosificación , Quinasas Ciclina-Dependientes/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Fenotipo , Medicina de Precisión/métodos , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/patología , Análisis de Supervivencia , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos
13.
Anticancer Res ; 40(9): 5091-5095, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32878797

RESUMEN

BACKGROUND/AIM: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel. RESULTS: Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo. CONCLUSION: Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Imidazoles/farmacología , Naftoquinonas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/genética , Survivin/genética , Taxoides/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , ARN Mensajero/genética , Ensayos Antitumor por Modelo de Xenoinjerto
14.
PLoS One ; 15(9): e0239686, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32997692

RESUMEN

INTRODUCTION: A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results. METHODS: We conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as ≥30%/≥50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods. RESULTS: A total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior surgery, and receipt of prior radiation therapy were comparable between carriers and non-carriers. There was no evidence that PSA30/PSA50 differed by HR gene mutational status. Median pPFS and crPFS ranged 3-14 months across treatment modalities, but there was no evidence either differed by HR gene mutational status (all p>0.05). There was also no difference in outcomes between those with BRCA2 or PALB2 mutations (n = 17) compared to those without HR repair mutations. CONCLUSION: HR gene mutational status was associated with comparable clinical outcomes following treatment with ARSIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.


Asunto(s)
Mutación , Neoplasias de la Próstata Resistentes a la Castración/genética , Reparación del ADN por Recombinación/genética , Anciano , Antineoplásicos/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteína BRCA2/genética , Quinasas Ciclina-Dependientes/genética , Resistencia a Antineoplásicos , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Humanos , Proteína Homóloga de MRE11/genética , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Supervivencia sin Progresión , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Inhibidores de la Síntesis de Esteroides/uso terapéutico
15.
PLoS One ; 15(9): e0232807, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32986721

RESUMEN

Here we have improved an existing mouse model of prostate cancer based on prostate-specific deletion of Pten and Trp53 by incorporating a Cre-activatable luciferase reporter. By coupling the deletion of those genes to the activation of a luciferase reporter, we were able to monitor tumor burden non-invasively over time. We show that, consistent with previous reports, deletion of both Pten and Trp53 on a C57BL/6 background accelerates tumor growth and results in both the loss of androgen receptor expression and castrate resistant tumors as compared with loss of Pten alone. Loss of Trp53 results in the development of sarcomatoid histology and the expression of markers of epithelial-to-mesenchymal transition Zeb1 and vimentin, with kinetics and penetrance dependent on whether one or both alleles of Trp53 were deleted. Homozygous deletion of Trp53 and Pten resulted in uniformly lethal disease by 25 weeks. While we were able to detect locally invasive disease in the peritoneal cavity in aggressive tumors from the double knockout mice, we were unable to detect lymphatic or hematogenous metastatic disease in lymph nodes or at distant sites.


Asunto(s)
Modelos Animales de Enfermedad , Fosfohidrolasa PTEN/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Eliminación de Secuencia , Proteína p53 Supresora de Tumor/genética , Animales , Biomarcadores de Tumor/genética , Carcinogénesis , Transición Epitelial-Mesenquimal , Mediciones Luminiscentes , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monitoreo Fisiológico
16.
PLoS One ; 15(9): e0226056, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32881870

RESUMEN

The androgen receptor (AR) is activated in patients with castration resistant prostate cancer (CRPC) despite low circulating levels of androgen, suggesting that intracellular signaling pathways and non-androgenic factors may contribute to AR activation. Many G-protein coupled receptors (GPCR) and their ligands are also activated in these cells indicating that they may play a role in development of Prostate Cancer (PCa) and CRPC. Although a cross talk has been suggested between the two pathways, yet, the identity of GPCRs which may play a role in androgen signaling, is not established yet. By using blast analysis of 826 GPCRs, we identified a GPCR, GPCR 205, which exhibited maximum similarity with the ligand binding domain of the AR. We demonstrate that adhesion GPCR 205, also known as GPR56, can be activated by androgens to stimulate the Rho signaling pathway, a pathway that plays an important role in prostate tumor cell metastasis. Testosterone stimulation of GPR56 also activates the cAMP/ Protein kinase A (PKA) pathway, that is necessary for AR signaling. Knocking down the expression of GPR56 using siRNA, disrupts nuclear translocation of AR and transcription of prototypic AR target genes such as PSA. GPR56 expression is higher in all twenty-five prostate tumor patient's samples tested and cells expressing GPR56 exhibit increased proliferation. These findings provide new insights about androgen signaling and identify GPR56 as a possible therapeutic target in advanced prostate cancer patients.


Asunto(s)
Andrógenos/metabolismo , Núcleo Celular/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Anciano , Animales , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Simulación del Acoplamiento Molecular , Próstata/citología , Próstata/patología , Próstata/cirugía , Prostatectomía , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/cirugía , ARN Interferente Pequeño/metabolismo , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/genética , Testosterona/metabolismo , Transcripción Genética
17.
Prostate ; 80(13): 1134-1144, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32628304

RESUMEN

BACKGROUND: Although androgen deprivation therapy (ADT) is the initial treatment strategy for prostate cancer (PCa), recurrent castration-resistant prostate cancer (CRPC) eventually ensues. In this study, cancer-derived immunoglobulin G (CIgG) is found to be induced after ADT, identifying CIgG as a potential CRPC driver gene. METHODS: The expression of CIgG and its clinical significance in PCa tissue was analyzed by The Cancer Genome Atlas database and immunohistochemistry. Subsequently, the sequence features of prostate cell line VHDJH rearrangements were analyzed. We also assessed the effect of CIgG on the migratory, invasive and proliferative abilities of PCa cells in vitro and vivo. Suspended microsphere, colony formation and drug-resistant assays were performed using PC3 cells with high CIgG expression (CIgGhigh ) and low CIgG expression (CIgG-/low ), and A nonobese diabetic/severe combined immunodeficiency mouse tumor xenograft model was developed for the study of the tumorigenic effects of the different cell populations. The SOX2-CIgG signaling pathway was validated by immunohistochemistry, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, Western blot, luciferase, and chromatin immunoprecipitation assays and bioinformatics analyses. Finally, we investigated the effect of RP215 inhibition on the progression of PCa in vivo using a Babl/c nude mouse xenograft model. RESULTS: CIgG is frequently expressed in PCa and associated with clinicopathological characteristics, moreover, CIgG transcripts with unique patterns of VHDJH rearrangements are found in PCa cells. Functional analyses identified that CIgG was induced by ADT and upregulated by SOX2 (SRY (sex determining region Y)-box 2) in PCa, promoting the development of PCa. In addition, our findings underscore a novel role of CIgG signaling in the maintenance of stemness and the progression of cancer through mitogen activated protein kinase/extracellular-signal-regulated kinase and AKT in PCa. In vivo experiments further demonstrated that depleting CIgG significantly suppressed the growth of PCa cell xenografts. Furthermore, a CIgG monoclonal antibody named RP215 exhibits tumor inhibitory effect as well. CONCLUSION: Our data suggests that CIgG could be a driver of PCa development, and that targeting the SOX2-CIgG axis may therefore inhibit PCa development after ADT.


Asunto(s)
Inmunoglobulina G/inmunología , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Factores de Transcripción SOXB1/inmunología , Animales , Células HEK293 , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Células PC-3 , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Factores de Transcripción SOXB1/biosíntesis , Factores de Transcripción SOXB1/genética , Transducción de Señal/inmunología , Análisis de Matrices Tisulares
18.
Prostate ; 80(13): 1108-1117, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32628318

RESUMEN

BACKGROUND: Putative castration-resistant (CR) stem-like cells (CRSC) have been identified based on their ability to initiate and drive prostate cancer (PCa) recurrence following castration in vivo. Yet the relevance of these CRSC in the course of the human disease and particularly for the transition from hormone-naive (HN) to castration-resistance is unclear. In this study, we aimed at deciphering the significance of CRSC markers in PCa progression. METHODS: We constructed a tissue microarray comprising 112 matched HN and CR tissue specimens derived from 55 PCa patients. Expression of eight stemness-associated markers (ALDH1A1, ALDH1A3, ALDH3A1, BMI1, NANOG, NKX3.1, OCT4, SOX2) was assessed by immunohistochemistry and scored as a percentage of positive tumor cells. For each marker, the resulting scores were statistically analyzed and compared to pathological and clinical data associated with the samples. Unsupervised clustering analysis was performed to stratify patients according to the expression of the eight CRSC markers. Publicly-available transcriptional datasets comprising HN and CR PCa samples were interrogated to assess the expression of the factors in silico. RESULTS: Immunohistochemical assessment of paired samples revealed atypical patterns of expression and intra- and intertumor heterogeneity for a subset of CRSC markers. While the expression of particular CRSC markers was dynamic over time in some patients, none of the markers showed significant changes in expression upon the development of castration resistance (CR vs HN). Using unsupervised clustering approaches, we identified phenotypic subtypes based on the expression of specific stem-associated markers. In particular, we found (a) patterns of mutual exclusivity for ALDH1A1 and ALDH1A3 expression, which was also observed at the transcriptomic level in publicly-available PCa datasets, and (b) a phenotypic cluster associated with more aggressive features. Finally, by comparing HN and CR matched samples, we identified phenotypic cluster switches (ie, change of phenotypic cluster between the HN and CR state), that may be associated with clinical and predictive relevance. CONCLUSIONS: Our findings indicate stemness-associated patterns that are associated with the development of castration-resistance. These results pave the way toward a deeper understanding of the relevance of CRSC markers in PCa progression and resistance to androgen-deprivation therapy.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , /genética , Aldehído Oxidorreductasas/genética , Aldehído Oxidorreductasas/metabolismo , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Heterogeneidad Genética , Humanos , Inmunohistoquímica , Masculino , Neoplasias de la Próstata Resistentes a la Castración/genética , Retinal-Deshidrogenasa/genética , Retinal-Deshidrogenasa/metabolismo , Análisis de Matrices Tisulares
19.
Prostate ; 80(12): 950-961, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32648618

RESUMEN

BACKGROUND: Prostate cancer is characterized by aberrant lipid metabolism, including elevated fatty acid oxidation. Carnitine palmitoyltransferase 1B (CPT1B) catalyzes the rate-limiting step of fatty acid oxidation. This study aimed to determine if CPT1B has a critical role in prostate cancer progression and to identify its regulatory mechanism. METHODS: CPT1B expression data from The Cancer Genome Atlas and Gene Expression Omnibus databases was compared with patient survival data. A tissue microarray was constructed with 60 samples of prostate cancer and immunohistochemically stained for CPT1B. Castration-resistant prostate cancer (CRPC) cell lines 22RV1 and C4-2 in which CPT1B expression had been stably knocked down were established; and cell proliferation, cell cycle distribution, and invasion were investigated by Cell Counting Kit-8 (CCK-8) and colony formation assays, flow cytometry, and Transwell assays, respectively. To examine the impact of androgen receptor (AR) inhibition on CPT1B expression, JASPAR CORE was searched to identify AR-binding sites in CPT1B. Dual luciferase and ChIP assays were performed to confirm CPT1B activity and AR binding, respectively. Differentially expressed genes (DEGs) in prostate cancer underwent gene set enrichment analysis (GSEA). Enzalutamide-resistant C4-2 cells were generated and the mechanism of enzalutamide resistance and downstream signaling pathway changes of CPT1B to C4-2 was explored through CCK-8 test. RESULTS: CPT1B expression was upregulated in human prostate cancer compared with normal prostate tissue and was associated with poor disease-free survival and overall survival. Silencing of CPT1B resulted in downregulated cell proliferation, reduced S-phase distribution, and lower invasive ability, whereas the opposite was observed in CRPC cells overexpressing CPTB1. DEGS in prostate cancer were correlated with G-protein-coupled receptor signaling, molecular transducer activity, and calcium ion binding. AR may regulate CPT1B expression and activity via specific binding sites, as confirmed by dual luciferase and ChIP assays. The CCK-8 experiment demonstrated that CPT1B overexpression in C4-2 cells did not significantly increase the ability of enzalutamide resistance. However, overexpression of CPT1B in C4-2R cells significantly increased the enzalutamide resistance. Upregulation of CPT1B expression increased AKT expression and phosphorylation. CONCLUSIONS: CPT1B is upregulated in prostate cancer and is correlated with poor prognosis, indicating its potential as a biomarker. AR inhibits the transcription of CPT1B. In the CRPC cell line, overexpression of CPT1B alone cannot promote enzalutamide resistance, but in the drug-resistant line C4-2R, overexpression of CPT1B can promote the resistance of C4-2R to enzalutamide.


Asunto(s)
Carnitina O-Palmitoiltransferasa/antagonistas & inhibidores , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/enzimología , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Estudios de Casos y Controles , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Progresión de la Enfermedad , Regulación hacia Abajo , Resistencia a Antineoplásicos , Humanos , Masculino , Terapia Molecular Dirigida , Feniltiohidantoína/farmacología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Transducción de Señal
20.
Prostate ; 80(12): 1012-1023, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32649013

RESUMEN

BACKGROUND: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9). CONCLUSION: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.


Asunto(s)
Células Neuroendocrinas/patología , Tumores Neuroendocrinos/patología , Neoplasias de la Próstata/patología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , Diferenciación Celular/fisiología , Estudios de Cohortes , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Células Neuroendocrinas/metabolismo , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Estudios Retrospectivos , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
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