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1.
Stem Cells ; 42(3): 173-199, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38096483

RESUMEN

The key role of cancer stem cells (CSCs) in tumor development and therapy resistance makes them essential biomarkers and therapeutic targets. Numerous agents targeting CSCs, either as monotherapy or as part of combination therapy, are currently being tested in clinical trials to treat solid tumors and hematologic malignancies. Data from ongoing and future clinical trials testing novel approaches to target tumor stemness-related biomarkers and pathways may pave the way for further clinical development of CSC-targeted treatments and CSC-guided selection of therapeutic regimens. In this concise review, we discuss recent progress in developing CSC-directed treatment approaches, focusing on clinical trials testing CSC-directed therapies. We also consider the further development of CSC-assay-guided patient stratification and treatment personalization.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Antineoplásicos/uso terapéutico , Neoplasias/terapia , Biomarcadores de Tumor/metabolismo , Células Madre Neoplásicas/metabolismo
2.
J Transl Med ; 22(1): 71, 2024 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-38238739

RESUMEN

The androgen receptor (AR) is a crucial player in various aspects of male reproduction and has been associated with the development and progression of prostate cancer (PCa). Therefore, the protein is the linchpin of current PCa therapies. Despite great research efforts, the AR signaling pathway has still not been deciphered, and the emergence of resistance is still the biggest problem in PCa treatment. To discuss the latest developments in AR research, the "1st International Androgen Receptor Symposium" offered a forum for the exchange of clinical and scientific innovations around the role of the AR in prostate cancer (PCa) and to stimulate new collaborative interactions among leading scientists from basic, translational, and clinical research. The symposium included three sessions covering preclinical studies, prognostic and diagnostic biomarkers, and ongoing prostate cancer clinical trials. In addition, a panel discussion about the future direction of androgen deprivation therapy and anti-AR therapy in PCa was conducted. Therefore, the newest insights and developments in therapeutic strategies and biomarkers are discussed in this report.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Receptores Androgénicos/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Antagonistas de Andrógenos/uso terapéutico , Transducción de Señal , Biomarcadores
3.
Semin Cancer Biol ; 82: 94-119, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-33290846

RESUMEN

Metabolic reprogramming is one of the main hallmarks of cancer cells. It refers to the metabolic adaptations of tumor cells in response to nutrient deficiency, microenvironmental insults, and anti-cancer therapies. Metabolic transformation during tumor development plays a critical role in the continued tumor growth and progression and is driven by a complex interplay between the tumor mutational landscape, epigenetic modifications, and microenvironmental influences. Understanding the tumor metabolic vulnerabilities might open novel diagnostic and therapeutic approaches with the potential to improve the efficacy of current tumor treatments. Prostate cancer is a highly heterogeneous disease harboring different mutations and tumor cell phenotypes. While the increase of intra-tumor genetic and epigenetic heterogeneity is associated with tumor progression, less is known about metabolic regulation of prostate cancer cell heterogeneity and plasticity. This review summarizes the central metabolic adaptations in prostate tumors, state-of-the-art technologies for metabolic analysis, and the perspectives for metabolic targeting and diagnostic implications.


Asunto(s)
Neoplasias de la Próstata , Epigénesis Genética , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo
4.
Int J Cancer ; 152(12): 2639-2654, 2023 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-36733230

RESUMEN

Ablative radiotherapy is a highly efficient treatment modality for patients with metastatic prostate cancer (PCa). However, a subset of patients does not respond. Currently, this subgroup with bad prognosis cannot be identified before disease progression. We hypothesize that markers indicative of radioresistance, stemness and/or bone tropism may have a prognostic potential to identify patients profiting from metastases-directed radiotherapy. Therefore, circulating tumor cells (CTCs) were analyzed in patients with metastatic PCa (n = 24) during radiotherapy with CellSearch, multicolor flow cytometry and imaging cytometry. Analysis of copy-number alteration indicates a polyclonal CTC population that changes after radiotherapy. CTCs were found in 8 out of 24 patients (33.3%) and were associated with a shorter time to biochemical progression after radiotherapy. Whereas the total CTC count dropped after radiotherapy, a chemokine receptor CXCR4-expressing subpopulation representing 28.6% of the total CTC population remained stable up to 3 months. At once, we observed higher chemokine CCL2 plasma concentrations and proinflammatory monocytes. Additional functional analyses demonstrated key roles of CXCR4 and CCL2 for cellular radiosensitivity, tumorigenicity and stem-like potential in vitro and in vivo. Moreover, a high CXCR4 and CCL2 expression was found in bone metastasis biopsies of PCa patients. In summary, panCK+ CXCR4+ CTCs may have a prognostic potential in patients with metastatic PCa treated with metastasis-directed radiotherapy.


Asunto(s)
Neoplasias Óseas , Células Neoplásicas Circulantes , Neoplasias de la Próstata , Masculino , Humanos , Células Neoplásicas Circulantes/patología , Biomarcadores de Tumor , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/patología , Pronóstico , Neoplasias Óseas/patología , Receptores CXCR4
5.
Cell Mol Life Sci ; 78(6): 3021-3044, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33230565

RESUMEN

Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms determining the sensitivity of intrinsically non-auxotrophic cancers to arginine deficiency are still poorly understood. We here show for the first time that arginine deficiency is accompanied by global metabolic changes and protein/membrane breakdown, and results in the induction of specific, more or less pronounced (severe vs. mild) ER stress responses in head and neck squamous cell carcinoma (HNSCC) cells that differ in their intrinsic ADT sensitivity. Combination of ADT with canavanine triggered catastrophic ER stress via the eIF2α-ATF4(GADD34)-CHOP pathway, thereby inducing apoptosis; the same signaling arm was irrelevant in ADT-related radiosensitization. The particular strong supra-additive effect of ADT, canavanine and irradiation in both intrinsically more and less sensitive cancer cells supports the rational of ER stress pathways as novel target for improving multi-modal metabolic anti-cancer therapy.


Asunto(s)
Canavanina/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Tolerancia a Radiación/efectos de los fármacos , Rayos X , Factor de Transcripción Activador 4/antagonistas & inhibidores , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Apoptosis/efectos de los fármacos , Arginina/deficiencia , Arginina/metabolismo , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Medios de Cultivo/química , Endorribonucleasas/antagonistas & inhibidores , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Factor 2 Eucariótico de Iniciación/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Factor de Transcripción CHOP/antagonistas & inhibidores , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo
6.
Int J Mol Sci ; 24(1)2022 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-36614114

RESUMEN

Docetaxel (DTX) is a mainstay in the treatment of metastatic prostate cancer. Failure of DTX therapy is often associated with multidrug resistance caused by overexpression of efflux membrane transporters of the ABC family such as the glycoprotein ABCB1. This study investigated multiple approaches targeting ABCB1 to resensitize DTX-resistant (DTXR) prostate cancer cell lines. In DU145 DTXR and PC-3 DTXR cells as well as age-matched parental controls, the expression of selected ABC transporters was analyzed by quantitative PCR, Western blot, flow cytometry and immunofluorescence. ABCB1 effluxing activity was studied using the fluorescent ABCB1 substrate rhodamine 123. The influence of ABCB1 inhibitors (elacridar, tariquidar), ABCB1-specific siRNA and inhibition of post-translational glycosylation on DTX tolerance was assessed by cell viability and colony formation assays. In DTXR cells, only ABCB1 was highly upregulated, which was accompanied by a strong effluxing activity and additional post-translational glycosylation of ABCB1. Pharmacological inhibition and siRNA-mediated knockdown of ABCB1 completely resensitized DTXR cells to DTX. Inhibition of glycosylation with tunicamycin affected DTX resistance partially in DU145 DTXR cells, which was accompanied by a slight intracellular accumulation and decreased effluxing activity of ABCB1. In conclusion, DTX resistance can be reversed by various strategies with small molecule inhibitors representing the most promising and feasible approach.


Asunto(s)
Antineoplásicos , Neoplasias de la Próstata , Masculino , Humanos , Docetaxel/farmacología , Docetaxel/uso terapéutico , Taxoides/uso terapéutico , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Interferente Pequeño/farmacología , Antineoplásicos/uso terapéutico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética
7.
PLoS Comput Biol ; 15(11): e1007460, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31682594

RESUMEN

Radiation therapy is an important and effective treatment option for prostate cancer, but high-risk patients are prone to relapse due to radioresistance of cancer cells. Molecular mechanisms that contribute to radioresistance are not fully understood. Novel computational strategies are needed to identify radioresistance driver genes from hundreds of gene copy number alterations. We developed a network-based approach based on lasso regression in combination with network propagation for the analysis of prostate cancer cell lines with acquired radioresistance to identify clinically relevant marker genes associated with radioresistance in prostate cancer patients. We analyzed established radioresistant cell lines of the prostate cancer cell lines DU145 and LNCaP and compared their gene copy number and expression profiles to their radiosensitive parental cells. We found that radioresistant DU145 showed much more gene copy number alterations than LNCaP and their gene expression profiles were highly cell line specific. We learned a genome-wide prostate cancer-specific gene regulatory network and quantified impacts of differentially expressed genes with directly underlying copy number alterations on known radioresistance marker genes. This revealed several potential driver candidates involved in the regulation of cancer-relevant processes. Importantly, we found that ten driver candidates from DU145 (ADAMTS9, AKR1B10, CXXC5, FST, FOXL1, GRPR, ITGA2, SOX17, STARD4, VGF) and four from LNCaP (FHL5, LYPLAL1, PAK7, TDRD6) were able to distinguish irradiated prostate cancer patients into early and late relapse groups. Moreover, in-depth in vitro validations for VGF (Neurosecretory protein VGF) showed that siRNA-mediated gene silencing increased the radiosensitivity of DU145 and LNCaP cells. Our computational approach enabled to predict novel radioresistance driver gene candidates. Additional preclinical and clinical studies are required to further validate the role of VGF and other candidate genes as potential biomarkers for the prediction of radiotherapy responses and as potential targets for radiosensitization of prostate cancer.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Recurrencia Local de Neoplasia/genética , Tolerancia a Radiación/genética , Apoptosis , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Biología Computacional/métodos , Dosificación de Gen/genética , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Silenciador del Gen , Humanos , Masculino , Factores de Crecimiento Nervioso/genética , Neoplasias de la Próstata/genética , ARN Mensajero/genética , ARN Interferente Pequeño , Recurrencia , Transducción de Señal/genética , Transcriptoma/genética
8.
Int J Cancer ; 145(11): 2974-2985, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30968962

RESUMEN

Prostate cancer (PCa) is the second most common malignancy and the sixth leading cause of cancer-related death among men worldwide. Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell transition between a stem- and nonstem-cell state and accelerate tumor evolution. Elevated expression of enhancer of zeste homolog 2 (EZH2) histone methyltransferase, a core member of the polycomb repressive complex 2 (PRC2), results in cancer progression through histone methylation-driven tumor cells dedifferentiation. Previous studies demonstrated that tumor suppressor breast cancer 1 (BRCA1) is a negative regulator of PRC2-dependent H3K27 methylation. Our recent studies revealed that inhibition of EZH2-mediated histone methylation radiosensitizes prostate cancer stem cells (CSCs) population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are coregulated in patients' tumors and PCa cell lines, and cooperate in regulation of CSC phenotype and properties. Knockdown of BRCA1 expression significantly increases the number and the size of tumor spheres. Inhibition of BRCA1 and EZH2 expression leads to an increase of aldehyde dehydrogenase (ALDH)-positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein. Treatment with a global histone methylation inhibitor 3-Deazaneplanocin A abrogates this regulation, downregulates BRCA1 and EZH2 expression and has an inhibitory effect on the tumorigenic properties of radioresistant PCa cells in vivo. We found that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSC properties and may be a promising target for tumor treatment.


Asunto(s)
Proteína BRCA1/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Células Madre Neoplásicas/patología , Neoplasias de la Próstata/patología , Aldehído Oxidorreductasas/metabolismo , Animales , Proteína BRCA1/genética , Línea Celular Tumoral , Proteína Potenciadora del Homólogo Zeste 2/genética , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Humanos , Masculino , Metilación , Ratones , Trasplante de Neoplasias , Células Madre Neoplásicas/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo
9.
Stem Cells ; 36(10): 1457-1474, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29845679

RESUMEN

Prostate cancer (PCa) is heterogeneous, harboring phenotypically diverse cancer cell types. PCa cell heterogeneity is caused by genomic instability that leads to the clonal competition and evolution of the cancer genome and by epigenetic mechanisms that result in subclonal cellular differentiation. The process of tumor cell differentiation is initiated from a population of prostate cancer stem cells (PCSCs) that possess many phenotypic and functional properties of normal stem cells. Since the initial reports on PCSCs in 2005, there has been much effort to elucidate their biological properties, including unique metabolic characteristics. In this Review, we discuss the current methods for PCSC enrichment and analysis, the hallmarks of PCSC metabolism, and the role of PCSCs in tumor progression. Stem Cells 2018;36:1457-1474.


Asunto(s)
Células Madre Neoplásicas/trasplante , Neoplasias de la Próstata/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Humanos , Masculino , Neoplasias de la Próstata/patología
10.
Semin Cancer Biol ; 44: 10-24, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28257956

RESUMEN

Metastatic tumors are the cause of more than 90% of cancer related deaths. Metastasis formation can be considered as a culmination of the Darwinian evolutionary process within the tumor, when competition of multiple clones results in the development of cell inherent traits that favor tumor dissemination. Cancer stem cells (CSC) which possess self-renewal properties and genomic instability are considered to be an engine of tumor evolution. Cancer cells which have the capacity to colonize distant organs have the features of CSC and, in addition, exert their tumor-initiating capacity under adverse microenvironmental conditions. Recent studies support an idea that metastases can be driven by the evolved and selected subpopulations of CSC. In this review we discuss the common hallmarks of CSC and metastasis initiating cells (MIC) and prospects for the development of anti-metastatic therapy.


Asunto(s)
Transición Epitelial-Mesenquimal/genética , Recurrencia Local de Neoplasia/genética , Neoplasias/genética , Células Madre Neoplásicas , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Humanos , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Neoplasias/patología
11.
Semin Cancer Biol ; 31: 16-27, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24956577

RESUMEN

Similar to normal tissue, many tumors have a hierarchical organization where tumorigenic cancer stem cells (CSCs) differentiate into non-tumorigenic progenies. A host of studies have demonstrated that although CSCs and their non-tumorigenic progenies within the same clone can share common genotype, they display different epigenetic profiles that results in changes of multiple signaling pathways. Many of these pathways confer cell adaptation to the microenvironmental stresses including inflammation, hypoxia, low pH, shortage in nutrients and anti-cancer therapies. Treatment strategies based on combination of conventional therapies targeting bulk tumor cells and CSC-specific pathway inhibition bear a promise to improve cancer cure compared to monotherapies. In this review we describe the mechanisms of CSC-related therapy resistance including drug efflux by ABC transporters, activation of aldehyde dehydrogenase and developmental pathways, enhanced DNA damage response, autophagy and microenvironmental conditions, and discuss possible therapeutic strategies for improving cancer treatment.


Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Transportadoras de Casetes de Unión a ATP/metabolismo , Antineoplásicos/metabolismo , Biomarcadores de Tumor/metabolismo , Humanos , Modelos Biológicos , Terapia Molecular Dirigida/métodos , Neoplasias/metabolismo , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal/efectos de los fármacos
12.
Proc Natl Acad Sci U S A ; 110(44): 17796-801, 2013 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-24127589

RESUMEN

Bispecific antibodies, which simultaneously target CD3 on T cells and tumor-associated antigens to recruit cytotoxic T cells to cancer cells, are a promising new approach to the treatment of hormone-refractory prostate cancer. Here we report a site-specific, semisynthetic method for the production of bispecific antibody-like therapeutics in which a derivative of the prostate-specific membrane antigen-binding small molecule DUPA was selectively conjugated to a mutant αCD3 Fab containing the unnatural amino acid, p-acetylphenylalanine, at a defined site. Homogeneous conjugates were generated in excellent yields and had good solubility. The efficacy of the conjugate was optimized by modifying the linker structure, relative binding orientation, and stoichiometry of the ligand. The optimized conjugate showed potent and selective in vitro activity (EC50 ~ 100 pM), good serum half-life, and potent in vivo activity in prophylactic and treatment xenograft mouse models. This semisynthetic approach is likely to be applicable to the generation of additional bispecific agents using drug-like ligands selective for other cell-surface receptors.


Asunto(s)
Descubrimiento de Drogas/métodos , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Complejo CD3/inmunología , Xenoinjertos/inmunología , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Inmunoterapia/métodos , Leucocitos Mononucleares , Masculino , Ratones , Neoplasias de la Próstata/inmunología , Ingeniería de Proteínas
13.
J Biol Chem ; 289(51): 35503-16, 2014 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-25371201

RESUMEN

The transcription factor Hes3 is a component of a signaling pathway that supports the growth of neural stem cells with profound consequences in neurodegenerative disease models. Here we explored whether Hes3 also regulates pancreatic islet cells. We showed that Hes3 is expressed in human and rodent pancreatic islets. In mouse islets it co-localizes with alpha and beta cell markers. We employed the mouse insulinoma cell line MIN6 to perform in vitro characterization and functional studies in conditions known to modulate Hes3 based upon our previous work using neural stem cell cultures. In these conditions, cells showed elevated Hes3 expression and nuclear localization, grew efficiently, and showed higher evoked insulin release responses, compared with serum-containing conditions. They also exhibited higher expression of the transcription factor Pdx1 and insulin. Furthermore, they were responsive to pharmacological treatments with the GLP-1 analog Exendin-4, which increased nuclear Hes3 localization. We employed a transfection approach to address specific functions of Hes3. Hes3 RNA interference opposed cell growth and affected gene expression as revealed by DNA microarrays. Western blotting and PCR approaches specifically showed that Hes3 RNA interference opposes the expression of Pdx1 and insulin. Hes3 overexpression (using a Hes3-GFP fusion construct) confirmed a role of Hes3 in regulating Pdx1 expression. Hes3 RNA interference reduced evoked insulin release. Mice lacking Hes3 exhibited increased islet damage by streptozotocin. These data suggest roles of Hes3 in pancreatic islet function.


Asunto(s)
Proliferación Celular , Proteínas de Unión al ADN/genética , Expresión Génica , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Factores de Transcripción/genética , Adulto , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Western Blotting , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Exenatida , Perfilación de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Hipoglucemiantes/farmacología , Insulina/genética , Secreción de Insulina , Insulinoma/genética , Insulinoma/metabolismo , Insulinoma/patología , Islotes Pancreáticos/citología , Islotes Pancreáticos/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Mutantes , Ratones Obesos , Microscopía Confocal , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Péptidos/farmacología , Interferencia de ARN , Proteínas Represoras , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Ponzoñas/farmacología
14.
Int J Cancer ; 137(10): 2492-503, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26059723

RESUMEN

Many tumors including prostate cancer are maintained by cancer stem cells (CSCs), which might cause tumor relapse if not eradicated during the course of treatment. Specific targeting or radiosensitization of CSCs bear promise to improve tumor curability by synergistic effects in combination with radiotherapy. Carbon nanotubes (CNTs) can be used as promising drug delivery systems for anticancer drugs such as the flavonoid catechin. Catechin is an extensively studied active ingredient of the different plants, including green tea, and it is widely recognized as co-adjuvant in cancer therapy. Here we describe the synthesis of biocompatible, catechin-loaded and gelatin-conjugated CNTs (Gel_CT_CNTs) with anticancer properties and demonstrate their potential for the eradication of prostate CSCs in combination with X-ray irradiation. Gel_CT_CNTs showed a significant enhancement of in vitro anticancer activity as compared to catechin alone. Moreover, treatment of prostate cancer cells with Gel_CT_CNT nanohybrids inhibited the tumorigenic cell population defined by a high aldehyde dehydrogenase (ALDH) activity. A combination of X-ray irradiation and treatment with Gel_CT_CNTs caused a decrease in the protein level of stem cell-related transcription factors and regulators including Nanog, Oct4 and ß-catenin and led to an increase of cancer cell radiosensitivity as demonstrated by clonogenic and spherogenic cell survival assays. Taken together, our results suggest that a combination of irradiation and Gel_CT_CNTs can be potentially used for the radiosensitization and eradication of prostate CSC populations.


Asunto(s)
Antineoplásicos/síntesis química , Catequina/química , Gelatina/química , Nanotubos de Carbono/química , Neoplasias de la Próstata/terapia , Fármacos Sensibilizantes a Radiaciones/síntesis química , Aldehído Deshidrogenasa/metabolismo , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular , Quimioradioterapia/métodos , Composición de Medicamentos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Trasplante de Neoplasias , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/efectos de la radiación , Neoplasias de la Próstata/patología , Fármacos Sensibilizantes a Radiaciones/administración & dosificación
15.
Cancers (Basel) ; 16(16)2024 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-39199642

RESUMEN

Glutamine (Gln) is a non-essential amino acid that is involved in the development and progression of several malignancies, including prostate cancer (PCa). While Gln is non-essential for non-malignant prostate epithelial cells, PCa cells become highly dependent on an exogenous source of Gln. The Gln metabolism in PCa is tightly controlled by well-described oncogenes such as MYC, AR, and mTOR. These oncogenes contribute to therapy resistance and progression to the aggressive castration-resistant PCa. Inhibition of Gln catabolism impedes PCa growth, survival, and tumor-initiating potential while sensitizing the cells to radiotherapy. Therefore, given its significant role in tumor growth, targeting Gln metabolism is a promising approach for developing new therapeutic strategies. Ongoing clinical trials evaluate the safety and efficacy of Gln catabolism inhibitors in combination with conventional and targeted therapies in patients with various solid tumors, including PCa. Further understanding of how PCa cells metabolically interact with their microenvironment will facilitate the clinical translation of Gln inhibitors and help improve therapeutic outcomes. This review focuses on the role of Gln in PCa progression and therapy resistance and provides insights into current clinical trials.

16.
Oncogene ; 43(26): 2038-2050, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38750263

RESUMEN

Docetaxel (DX) serves as a palliative treatment option for metastatic prostate cancer (PCa). Despite initial remission, acquired DX resistance is inevitable. The mechanisms behind DX resistance have not yet been deciphered, but a mesenchymal phenotype is associated with DX resistance. Mesenchymal phenotypes have been linked to metabolic rewiring, obtaining most ATP production by oxidative phosphorylation (OXPHOS) powered substantially by glutamine (Gln). Likewise, Gln is known to play an essential role in modulating bioenergetic, redox homeostasis and autophagy. Herein, investigations of Gln deprivation on DX-sensitive and -resistant (DR) PCa cells revealed that the DR cell sub-lines were susceptible to Gln deprivation. Mechanistically, Gln deprivation reduced OXPHOS and ATP levels, causing a disturbance in cell cycle progression. Genetic and chemical inhibition of the Gln-metabolism key protein GLS1 could validate the Gln deprivation results, thereby representing a valid therapeutic target. Moreover, immunohistological investigation of GLS1 revealed a high-expressing GLS1 subgroup post-docetaxel failure, exhibiting low overall survival. This subgroup presents an intriguing opportunity for targeted therapy focusing on glutamine metabolism. Thus, these findings highlight a possible clinical rationale for the chemical inhibition of GLS1 as a therapeutic strategy to target mesenchymal DR PCa cells, thereby delaying accelerated tumour progression.


Asunto(s)
Proliferación Celular , Docetaxel , Resistencia a Antineoplásicos , Glutamina , Neoplasias de la Próstata , Masculino , Humanos , Glutamina/metabolismo , Docetaxel/farmacología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Fosforilación Oxidativa/efectos de los fármacos , Glutaminasa/metabolismo , Glutaminasa/antagonistas & inhibidores , Glutaminasa/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico
17.
Front Cell Dev Biol ; 12: 1452463, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39149513

RESUMEN

Radiotherapy of prostate cancer (PC) can lead to the acquisition of radioresistance through molecular mechanisms that involve, in part, cell adhesion-mediated signaling. To define these mechanisms, we employed a DU145 PC model to conduct a comparative mass spectrometry-based proteomic analysis of the purified integrin nexus, i.e., the cell-matrix junction where integrins bridge assembled extracellular matrix (matrisome components) to adhesion signaling complexes (adhesome components). When parental and radioresistant cells were compared, the expression of integrins was not changed, but cell radioresistance was associated with extensive matrix remodeling and changes in the complement of adhesion signaling proteins. Out of 72 proteins differentially expressed in the parental and radioresistant cells, four proteins were selected for functional validation based on their correlation with biochemical recurrence-free survival. Perlecan/heparan sulfate proteoglycan 2 (HSPG2) and lysyl-like oxidase-like 2 (LOXL2) were upregulated, while sushi repeat-containing protein X-linked (SRPX) and laminin subunit beta 3 (LAMB3) were downregulated in radioresistant DU145 cells. Knockdown of perlecan/HSPG2 sensitized radioresistant DU145 RR cells to irradiation while the sensitivity of DU145 parental cells did not change, indicating a potential role for perlecan/HSPG2 and its associated proteins in suppressing tumor radioresistance. Validation in androgen-sensitive parental and radioresistant LNCaP cells further supported perlecan/HSPG2 as a regulator of cell radiosensitivity. These findings extend our understanding of the interplay between extracellular matrix remodeling and PC radioresistance and signpost perlecan/HSPG2 as a potential therapeutic target and biomarker for PC.

18.
Cancers (Basel) ; 16(4)2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38398123

RESUMEN

(1) Background: The sensitivity of head and neck squamous cell carcinoma (HNSCC) to ionizing radiation, among others, is determined by the number of cells with high clonogenic potential and stem-like features. These cellular characteristics are dynamically regulated in response to treatment and may lead to an enrichment of radioresistant cells with a cancer stem cell (CSC) phenotype. Epigenetic mechanisms, particularly DNA and histone methylation, are key regulators of gene-specific transcription and cellular plasticity. Therefore, we hypothesized that specific epigenetic targeting may prevent irradiation-induced plasticity and may sensitize HNSCC cells to radiotherapy. (2) Methods: We compared the DNA methylome and intracellular concentrations of tricarboxylic acid cycle metabolites in radioresistant FaDu and Cal33 cell lines with their parental controls, as well as aldehyde dehydrogenase (ALDH)-positive CSCs with negative controls. Moreover, we conducted a screen of a chemical library targeting enzymes involved in epigenetic regulation in combination with irradiation and analyzed the clonogenic potential, sphere formation, and DNA repair capacity to identify compounds with both radiosensitizing and CSC-targeting potential. (3) Results: We identified the histone demethylase inhibitor GSK-J1, which targets UTX (KDM6A) and JMJD3 (KDM6B), leading to increased H3K27 trimethylation, heterochromatin formation, and gene silencing. The clonogenic survival assay after siRNA-mediated knock-down of both genes radiosensitized Cal33 and SAS cell lines. Moreover, high KDM6A expression in tissue sections of patients with HNSCC was associated with improved locoregional control after primary (n = 137) and post-operative (n = 187) radio/chemotherapy. Conversely, high KDM6B expression was a prognostic factor for reduced overall survival. (4) Conclusions: Within this study, we investigated cellular and molecular mechanisms underlying irradiation-induced cellular plasticity, a key inducer of radioresistance, with a focus on epigenetic alterations. We identified UTX (KDM6A) as a putative prognostic and therapeutic target for HNSCC patients treated with radiotherapy.

19.
Theranostics ; 14(2): 714-737, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38169509

RESUMEN

Rationale: Current therapies for metastatic osseous disease frequently fail to provide a durable treatment response. To date, there are only limited therapeutic options for metastatic prostate cancer, the mechanisms that drive the survival of metastasis-initiating cells are poorly characterized, and reliable prognostic markers are missing. A high aldehyde dehydrogenase (ALDH) activity has been long considered a marker of cancer stem cells (CSC). Our study characterized a differential role of ALDH1A1 and ALDH1A3 genes as regulators of prostate cancer progression and metastatic growth. Methods: By genetic silencing of ALDH1A1 and ALDH1A3 in vitro, in xenografted zebrafish and murine models, and by comparative immunohistochemical analyses of benign, primary tumor, and metastatic specimens from patients with prostate cancer, we demonstrated that ALDH1A1 and ALDH1A3 maintain the CSC phenotype and radioresistance and regulate bone metastasis-initiating cells. We have validated ALDH1A1 and ALDH1A3 as potential biomarkers of clinical outcomes in the independent cohorts of patients with PCa. Furthermore, by RNAseq, chromatin immunoprecipitation (ChIP), and biostatistics analyses, we suggested the molecular mechanisms explaining the role of ALDH1A1 in PCa progression. Results: We found that aldehyde dehydrogenase protein ALDH1A1 positively regulates tumor cell survival in circulation, extravasation, and metastatic dissemination, whereas ALDH1A3 plays the opposite role. ALDH1A1 and ALDH1A3 are differentially expressed in metastatic tumors of patients with prostate cancer, and their expression levels oppositely correlate with clinical outcomes. Prostate cancer progression is associated with the increasing interplay of ALDH1A1 with androgen receptor (AR) and retinoid receptor (RAR) transcriptional programs. Polo-like kinase 3 (PLK3) was identified as a transcriptional target oppositely regulated by ALDH1A1 and ALDH1A3 genes in RAR and AR-dependent manner. PLK3 contributes to the control of prostate cancer cell proliferation, migration, DNA repair, and radioresistance. ALDH1A1 gain in prostate cancer bone metastases is associated with high PLK3 expression. Conclusion: This report provides the first evidence that ALDH1A1 and PLK3 could serve as biomarkers to predict metastatic dissemination and radiotherapy resistance in patients with prostate cancer and could be potential therapeutic targets to eliminate metastasis-initiating and radioresistant tumor cell populations.


Asunto(s)
Neoplasias de la Próstata , Receptores Androgénicos , Masculino , Humanos , Animales , Ratones , Pez Cebra/metabolismo , Línea Celular Tumoral , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa/metabolismo , Neoplasias de la Próstata/genética , Biomarcadores , Familia de Aldehído Deshidrogenasa 1 , Retinal-Deshidrogenasa
20.
Front Oncol ; 13: 1251100, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37823053

RESUMEN

The SLC3A2 gene encodes for a cell-surface transmembrane protein CD98hc (4F2). CD98hc serves as a chaperone for LAT1 (SLC7A5), LAT2 (SLC7A8), y+LAT1 (SLC7A7), y+LAT2 (SLC7A6), xCT (SLC7A11) and Asc1 (SLC7A10) providing their recruitment to the plasma membrane. Together with the light subunits, it constitutes heterodimeric transmembrane amino acid transporters. CD98hc interacts with other surface molecules, such as extracellular matrix metalloproteinase inducer CD147 (EMMPRIN) and adhesion receptors integrins, and regulates glucose uptake. In this way, CD98hc connects the signaling pathways sustaining cell proliferation and migration, biosynthesis and antioxidant defense, energy production, and stem cell properties. This multifaceted role makes CD98hc one of the critical regulators of tumor growth, therapy resistance, and metastases. Indeed, the high expression levels of CD98hc were confirmed in various tumor tissues, including head and neck squamous cell carcinoma, glioblastoma, colon adenocarcinoma, pancreatic ductal adenocarcinoma, and others. A high expression of CD98hc has been linked to clinical prognosis and response to chemo- and radiotherapy in several types of cancer. In this mini-review, we discuss the physiological functions of CD98hc, its role in regulating tumor stemness, metastases, and therapy resistance, and the clinical significance of CD98hc as a tumor marker and therapeutic target.

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