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1.
Biol Res ; 53(1): 18, 2020 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-32349783

RESUMEN

BACKGROUND: Cisplatin resistance (DDP-resistance) remains one of the major causes of poor prognosis in females with ovarian cancer. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of cellular processes, including chemoresistance. The aim of this study was to explore the role of HOX transcript antisense RNA (HOTAIR) in DDP-resistant ovarian cancer cells. METHODS: DDP-resistant ovarian cancer cell lines (SKOV3/DDP and A2780/DDP) were established. Real-time PCR, western blot, dual-luciferase reporter assay, and flow cytometry were then used to evaluate the effect of HOTAIR/miR-138-5p axis on chemoresistance of DDP-resistant ovarian cancer cells to DDP. RESULTS: We found that HOTAIR was upregulated in DDP-resistant cells, while miR-138-5p was downregulated. Knockdown of HOTAIR increased the expression of miR-138-5p in DDP-resistant cells and miR-138-5p is directly bound to HOTAIR. Upregulation of miR-138-5p induced by HOTAIR siRNA or by its mimics enhanced the chemosensitivity of DDP-resistant cells and decreased the expression of EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) and SIRT1 (sirtuin 1). Furthermore, the HOTAIR silencing-induced chemosensitivity of DDP-resistant cells was weakened by miR-138-5p inhibitor. CONCLUSIONS: These data demonstrate that HOTAIR acts as a sponge of miR-138-5p to prevent its binding to EZH2 and SIRT1, thereby promoting DDP-resistance of ovarian cancer cells. Our work will shed light on the development of therapeutic strategies for ovarian cancer treatment.


Asunto(s)
Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Neoplasias Ováricas/genética , ARN Largo no Codificante/genética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes/métodos , Humanos , MicroARNs/antagonistas & inhibidores , Reacción en Cadena en Tiempo Real de la Polimerasa , Sirtuina 1/antagonistas & inhibidores , Regulación hacia Arriba
2.
Anticancer Res ; 40(5): 2457-2465, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32366389

RESUMEN

The introduction of tyrosine kinase inhibitors (TKIs) directed against the catalytic activity of the ABL tyrosine kinase has considerably improved the outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease. Indeed, these individuals currently show a life-expectancy comparable to those of healthy subjects. Currently, five TKIs (imatinib, dasatinib, nilotinib, bosutinib and ponatinib) are approved for the treatment of CML and can be used as first, second or further lines of treatment according to disease risk scores, patient comorbidities and the presence of known TKI resistance mechanisms. In fact, 15-20% of all CML patients fail to achieve optimal responses according to the current definitions of the European Leukemia Network and will require sequential TKI treatment to avoid disease progression. In this review, we present the state of art in several crucial areas of CML management by briefly: i) depicting the domain structure of the BCR-ABL1 oncoprotein; ii) describing pivotal data concerning TKI efficacy; iii) illustrating the diverse molecular mechanisms causing TKI resistance; and iv) summarizing new ABL1-directed therapeutic approaches that are presently under investigation.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-abl/genética , Resultado del Tratamiento
3.
Adv Exp Med Biol ; 1233: 153-174, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32274756

RESUMEN

Since its introduction in the clinics in early 2000s, the proteasome inhibitor bortezomib (BTZ) significantly improved the prognosis of patients with multiple myeloma (MM) and mantle cell lymphoma (MCL), two of the most challenging B cell malignancies in western countries. However, relapses following BTZ therapy are frequent, while primary resistance to this agent remains a major limitation for further development of its therapeutic potential. In the present chapter, we recapitulate the molecular mechanisms associated with intrinsic and acquired resistance to BTZ learning from MM and MCL experience, including mutations of crucial genes and activation of prosurvival signalling pathways inherent to malignant B cells. We also outline the preclinical and clinical evaluations of some potential druggable targets associated to BTZ resistance, considering the most meaningful findings of the past 10 years. Although our understanding of BTZ resistance is far from being completed, recent discoveries are contributing to develop new approaches to treat relapsed MM and MCL patients.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Linfoma de Células del Manto/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Resistencia a Antineoplásicos/genética , Humanos , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia , Complejo de la Endopetidasa Proteasomal/metabolismo
4.
Anticancer Res ; 40(4): 1855-1866, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234873

RESUMEN

BACKGROUND/AIM: The resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, is considered a major challenge in the treatment of patients with non-small cell lung cancer (NSCLC). Herein, we identified the critical roles of anterior gradient 2 (AGR2) in gefitinib (Gef) resistance of mutant NSCLC cells. MATERIALS AND METHODS: Using datasets from a pair of NSCLC-sensitive and NSCLC-resistant cells, immunoblotting, immunofluorescence and immunohistochemistry, and cell viability assays were applied to identify the effects of AGR2. RESULTS: AGR2 was found to be significantly over-expressed in Gef-resistant cells and was highly associated with drug resistance, proliferation, migration, and invasion of cancer cells. Moreover, AGR2 and ADAMTS6 formed a negative feedback loop in drug-resistant cells. CONCLUSION: Modulation of overexpression of AGR2 in mutant NSCLC cells may be an attractive therapeutic strategy for the treatment of EGFR-TKI-resistant NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Mucoproteínas/genética , Proteínas Oncogénicas/genética , Inhibidores de Proteínas Quinasas/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/farmacología , Gefitinib/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mutación , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Quinazolinas/farmacología
5.
Anticancer Res ; 40(4): 1897-1904, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32234878

RESUMEN

BACKGROUND/AIM: We investigated the clinical role of the molecular targets, APEX1 and Jagged-1, and the Apex1 - Jagged-1 cascade in gastric cancer cells. MATERIALS AND METHODS: We used 6 human gastric cancer cell lines (SNU-1, SNU-5, SNU-16, NCI-N87, KATO- III and AGS), and demonstrated the chemosensitivity of APEX1 and Jagged-1 through the MTT assay and immunoblotting. Tumor growth was assayed following cisplatin and 5-FU treatment using a xenograft model injected with KATO-III cells. Moreover, gastric tumor samples from 9 patients, divided in 2 groups according to chemotherapy response, were examined by immunocytochemical (IHC) staining, and protein expression levels were scored. RESULTS: Following APEX1 knockdown, the MTT assay revealed that the IC50 of cisplatin and 5-FU in AGS cells was decreased approximately 7% and 15%, respectively, however, their decrease in chemoresistant KATO-III cells was decreased by approximately 21% and 67% for cisplatin and 5-FU, respectively. The tumor volume of KATO-III/sicontrol mice treated with cisplatin and 5-FU was affected less, compared with KATO-III/siAPEX1 mice treated with cisplatin and 5-FU. Also, the expression levels of APEX1, Jagged-1 and CD133, assayed by IHC staining, were higher in the chemorefractory group than in the chemoresponsive group. CONCLUSION: Jagged-1-activated signaling by APEX1 plays a role in advanced gastric cancer.


Asunto(s)
ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Resistencia a Antineoplásicos/genética , Proteína Jagged-1/genética , Neoplasias Gástricas/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Fluorouracilo/farmacología , Humanos , Ratones , Estadificación de Neoplasias , Estómago/efectos de los fármacos , Estómago/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Semin Oncol ; 47(1): 73-84, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32201016

RESUMEN

Soft-tissue sarcomas (STS) are a group of rare mesenchymal tumors that constitutes ∼1% of all solid tumors. It remains a rare tumor which lacks effective treatment options. Precision oncology may be of interest in this regard by identifying potential targets for emerging novel therapies. Neurotrophic receptor tyrosine kinase (NTRK) fusions are rare oncogenic driver mutations found in a broad range of common and rare tumor subtypes including STS. The recent approvals of NTRK inhibitors (larotrectinib and entrectinib) represent new therapeutic options in the drug armamentarium especially valuable in advanced STS given the paucity of treatment options and the generally poor prognosis of these tumors. We review the methods used to detect NTRK fusions in STS with focus on incidence, diagnosis and management of these rare and intriguing oncogenic targets.


Asunto(s)
Biomarcadores de Tumor , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Sarcoma/tratamiento farmacológico , Sarcoma/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos/genética , Pruebas Genéticas , Humanos , Terapia Molecular Dirigida , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Sarcoma/diagnóstico , Sarcoma/epidemiología , Resultado del Tratamiento
7.
DNA Cell Biol ; 39(4): 724-732, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32213078

RESUMEN

Long noncoding RNA growth-arrest-specific transcript 5 (GAS5) has been proved to play a crucial role in cancer chemoresistance. However, the function of GAS5 and its underlying molecular mechanism in hepatocellular carcinoma (HCC) chemoresistance remain unknown. In this study, we aimed to investigate its function and underlying molecular mechanism in HCC cisplatin (CDDP) resistance. The results demonstrated that GAS5 was significantly downregulated in HCC tissues and cells, especially in CDDP-resistant HCC tissues and cells. Low GAS5 expression was tightly correlated with shorter survival in patients with HCC. Functionally, GAS5 overexpression sensitized CDDP-resistant HepG2/CDDP and Huh7/CDDP cells to CDDP. Mechanically, GAS5 improved the sensitivity of HCC cells to CDDP through sponging miR-222. Taken together, these observations suggested that overexpression of GAS5 overcame CDDP resistance of HCC cells by regulating miR-222, providing a potential therapeutic target for overcoming the chemoresistance of HCC cells.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/genética , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico
8.
Nat Commun ; 11(1): 740, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32029739

RESUMEN

Primary and acquired drug resistance imposes a major threat to achieving optimized clinical outcomes during cancer treatment. Aberrant changes in epigenetic modifications are closely involved in drug resistance of tumor cells. Using BET inhibitor (BETi) resistant leukemia cells as a model system, we demonstrated herein that genome-wide enhancer remodeling played a pivotal role in driving therapeutic resistance via compensational re-expression of pro-survival genes. Capitalizing on the CRISPR interference technology, we identified the second intron of IncRNA, PVT1, as a unique bona fide gained enhancer that restored MYC transcription independent of BRD4 recruitment in leukemia. A combined BETi and CDK7 inhibitor treatment abolished MYC transcription by impeding RNAPII loading without affecting PVT1-mediated chromatin looping at the MYC locus in BETi-resistant leukemia cells. Together, our findings have established the feasibility of targeting enhancer plasticity to overcome drug resistance associated with epigenetic therapies.


Asunto(s)
Leucemia Experimental/tratamiento farmacológico , Leucemia Experimental/genética , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Animales , Proteínas de Ciclo Celular/antagonistas & inhibidores , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Elementos de Facilitación Genéticos , Femenino , Genes myc/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Humanos , Células Jurkat , Células K562 , Leucemia Experimental/metabolismo , Ratones , Modelos Genéticos , Fenilendiaminas/administración & dosificación , Pirimidinas/administración & dosificación , ARN Polimerasa II/metabolismo , ARN Largo no Codificante/genética
9.
Cancer Sci ; 111(4): 1047-1057, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32060987

RESUMEN

The roles of cancer-associated fibroblasts (CAF) in the progression of various types of cancers are well established. CAF promote cancer progression through pleiotropic mechanisms, including the secretion of soluble factors and extracellular matrix, physical interactions with cancer cells, and the regulation of angiogenesis, immunity and metabolism. Their contribution to therapeutic resistance is also well appreciated. Therefore, CAF have been considered as a therapeutic target in cancer. However, recent studies in autochthonous pancreatic cancer models suggest that specific subset(s) of CAF exhibit cancer-restraining roles, indicating that CAF are functionally and molecularly heterogeneous, which is supported by recent single-cell transcriptome analyses. While cancer-promoting CAF (pCAF) have been extensively studied, the nature and specific marker(s) of cancer-restraining CAF (rCAF) have remained uncharacterized. Interestingly, a recent study provided insight into the nature of rCAF and suggested that they may share molecular properties with pancreatic stellate cells (PSC) and mesenchymal stem/stromal cells (MSC). Complicating this finding is that PSC and MSC have been shown to promote the formation of a tumor-permissive and tumor-promoting environment in xenograft tumor models. However, these cells undergo significant transcriptional and epigenetic changes during ex vivo culture, which confounds the interpretation of experimental results based on the use of cultured cells. In this short review, we describe recent studies and hypotheses on the identity of rCAF and discuss their analogy to fibroblasts that suppress fibrosis in fibrotic diseases. Finally, we discuss how these findings can be exploited to develop novel anticancer therapies in the future.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Transformación Celular Neoplásica/genética , Neoplasias/genética , Neovascularización Patológica/genética , Animales , Fibroblastos Asociados al Cáncer/patología , Resistencia a Antineoplásicos/genética , Matriz Extracelular/genética , Xenoinjertos , Humanos , Células Madre Mesenquimatosas/metabolismo , Ratones , Neoplasias/patología , Neovascularización Patológica/patología , Células Estrelladas Pancreáticas/metabolismo , Microambiente Tumoral/genética
10.
Gene ; 738: 144453, 2020 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-32035242

RESUMEN

Breast cancer (BC) is the most common cancer among women that is responsible for the most of the cancer-related death in worldwide. Drug resistance is remaining as a significant clinical obstacle to treat BC patients effectively. Therefore, to help overcome this problem, it is necessary to understand the mechanisms of drug resistance. microRNAs classify as highly conserved non-coding RNAs (~22 nucleotides) and interact with mRNAs-coding genes for direct post-transcriptional repression. It has been reported that miR-21 is overexpressed and also acts as oncomiR in many human malignancies by targeting of several tumor suppressor genes-associated with apoptosis, proliferation and metastasis. Specifically, it has been reported that miR-21 is responsible for the drug resistance and its overexpression is related to the development of Multi Drug Resistance (MDR) in breast cancer. In this review, we discussed about the role of miR-21 on the drug resistance of breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , MicroARNs/genética , Apoptosis/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular/genética , Resistencia a Antineoplásicos/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Genes Supresores de Tumor , Humanos , MicroARNs/metabolismo , Metástasis de la Neoplasia/genética , Oncogenes/genética , ARN Mensajero/genética , Transducción de Señal/genética
11.
Nat Commun ; 11(1): 931, 2020 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-32071302

RESUMEN

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Glioma/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Animales , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-1/inmunología , Antígeno B7-1/metabolismo , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/inmunología , Femenino , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/inmunología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Imagen por Resonancia Magnética , Masculino , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología
12.
PLoS One ; 15(2): e0229077, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32069320

RESUMEN

Epidermal growth factor receptor (EGFR) is a pro-tumorigenic receptor tyrosine kinase that facilitates growth for cancer cells that overexpress the receptor. Monoclonal anti-EGFR antibody Cetuximab (CTX) provides significant clinical benefit in patients with head and neck squamous cell carcinoma (HNSCC). Missense mutations in the ectodomain (ECD) of EGFR can be acquired under CTX treatment and mimic the effect of large deletions on spontaneous untethering and activation of the receptor. Little is known about the contribution of EGFR ECD mutations to EGFR activation and CTX resistance in HNSCC. We identified two concurrent non-synonymous missense mutations (G33S and N56K) mapping to domain I in or near the EGF binding pocket of the EGFR ECD in patient-derived HNSCC cells that were selected for CTX resistance through repeated exposure to the agent in an effort to mimic what may occur clinically. Structural modeling predicted that the G33S and N56K mutants would restrict adoption of a fully closed (tethered) and inactive EGFR conformation while not permitting association of EGFR with the EGF ligand or CTX. Binding studies confirmed that the mutant, untethered receptor displayed reduced affinity for both EGF and CTX but demonstrated sustained activation and presence at the cell surface with diminished internalization and sorting for endosomal degradation, leading to persistent downstream AKT signaling. Our results demonstrate that HNSCC cells can select for EGFR ECD mutations under CTX exposure that converge to trap the receptor in an open, ligand-independent, constitutively activated state. These mutants impede the receptor's competence to bind CTX possibly explaining certain cases of CTX treatment-induced or de novo resistance to CTX.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Cetuximab/farmacología , Resistencia a Antineoplásicos/genética , Neoplasias de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Antineoplásicos Inmunológicos/uso terapéutico , Cetuximab/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Factor de Crecimiento Epidérmico/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Humanos , Ligandos , Modelos Moleculares , Mutación Missense , Cultivo Primario de Células , Dominios Proteicos/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Células Tumorales Cultivadas
13.
PLoS One ; 15(2): e0229104, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32106243

RESUMEN

Tyrosine kinase inhibitor (TKI) resistance is a major problem in chronic myeloid leukemia (CML). We generated a TKI-resistant K562 sub-population, K562-IR, under selective imatinib-mesylate pressure. K562-IR cells are CD34-/CD38-, BCR-Abl-independent, proliferate slowly, highly adherent and form intact tumor spheroids. Loss of CD45 and other hematopoietic markers reveal these cells have diverged from their hematopoietic origin. CD34 negativity, high expression of E-cadherin and CD44; decreased levels of CD45 and ß-catenin do not fully confer with the leukemic stem cell (LSC) phenotype. Expression analyses reveal that K562-IR cells differentially express tissue/organ development and differentiation genes. Our data suggest that the observed phenotypic shift is an adaptive process rendering cells under TKI stress to become oncogene independent. Cells develop transcriptional instability in search for a gene expression framework suitable for new environmental stresses, resulting in an adaptive phenotypic shift in which some cells partially display LSC-like properties. With leukemic/cancer stem cell targeted therapies underway, the difference between treating an entity and a spectrum of dynamic cellular states will have conclusive effects on the outcome.


Asunto(s)
Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Inhibidores de Proteínas Quinasas/farmacología , Células 3T3 , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/metabolismo , Perfilación de la Expresión Génica , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Ratones , Mutación/efectos de los fármacos , Análisis de Secuencia por Matrices de Oligonucleótidos , Dominios Proteicos/genética , Inhibidores de Proteínas Quinasas/uso terapéutico
14.
Mol Carcinog ; 59(4): 447-461, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32096299

RESUMEN

Effective therapeutic targets for triple-negative breast cancer (TNBC), a special type of breast cancer (BC) with rapid metastasis and poor prognosis, are lacking, especially for patients with chemotherapy resistance. Decitabine (DCA) is a Food and Drug Administration-approved DNA methyltransferase inhibitor that has been proven effective for the treatment of tumors. However, its antitumor effect in cancer cells is limited by multidrug resistance. Cancer stem cells (CSCs), which are thought to act as seeds during tumor formation, regulate tumorigenesis, metastasis, and drug resistance through complex signaling. Our previous study found that miR-155 is upregulated in BC, but whether and how miR-155 regulates DCA resistance is unclear. In this study, we demonstrated that miR-155 was upregulated in CD24- CD44+ BC stem cells (BCSCs). In addition, the overexpression of miR-155 increased the number of CD24- CD44+ CSCs, DCA resistance and tumor clone formation in MDA-231 and BT-549 BC cells, and knockdown of miR-155 inhibited DCA resistance and stemness in BCSCs in vitro. Moreover, miR-155 induced stemness and DCA resistance by inhibiting the direct target gene tetraspanin-5 (TSPAN5). We further confirmed that overexpression of TSPAN5 abrogated the effect of miR-155 in promoting stemness and DCA resistance in BC cells. Our data show that miR-155 increases stemness and DCA resistance in BC cells by targeting TSPAN5. These data provide a therapeutic strategy and mechanistic basis for future possible clinical applications targeting the miR-155/TSPAN5 signaling axis in the treatment of TNBC.


Asunto(s)
Decitabina/farmacología , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Células Madre Neoplásicas/metabolismo , Tetraspaninas/genética , Neoplasias de la Mama Triple Negativas/genética , Antimetabolitos Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tetraspaninas/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología
15.
Mol Pharmacol ; 97(4): 237-249, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32063580

RESUMEN

Dysfunction of p53 and resistance to cancer drugs can arise through mutually exclusive overexpression of MDM2 or MDM4. Cisplatin-resistant cells, however, can demonstrate increased binding of both MDM2 and MDM4 to p53 but in absence of cellular overexpression. Whether MDM2 inhibitors alone can activate p53 in these resistant cells was investigated with the goal to establish the mechanism for potential synergy with cisplatin. Thus, growth inhibition by individual drugs and combinations was assessed by a colorimetric assay. Drug-treated parental A2780 and resistant tumor cells were also examined for protein expression using immunoblot and reverse phase protein array (RPPA) and then subjected to Ingenuity Pathway Analysis (IPA). Gene expression was assessed by real-time polymerase chain reaction, DNA damage by confocal microscopy, cell cycle by flow cytometry, and homologous recombination (HR) by a GFP reporter assay. Our results demonstrate that Nutlin-3 but not RITA (reactivation of p53 and induction of tumor cell apoptosis) effectively disrupted the p53-MDM2-MDM4 complex to activate p53, which increased robustly with cisplatin/Nutlin-3 combination and enhanced antitumor effects more than either agent alone. RPPA, IPA, and confocal microscopy provided evidence for an "apparent" increase in DNA damage resulting from HR inhibition by cisplatin/Nutlin-3. Molecularly, the specific HR protein Rad51 was severely downregulated by the combination via two mechanisms: p53-dependent transrepression and p53/MDM2-mediated proteasomal degradation. In conclusion, Nutlin-3 fully destabilizes the p53-MDM2-MDM4 complex and synergizes with cisplatin to intensify p53 function, which then downregulates Rad51 through a bimodal mechanism. As a result, HR is inhibited and antitumor activity enhanced in otherwise HR-proficient sensitive and resistant tumor cells. SIGNIFICANCE STATEMENT: Rad51 downregulation by the combination of cisplatin and Nutlin-3 inhibits homologous recombination (HR), which leads to persistence in DNA damage but not an increase. Thus, inhibition of HR enhances antitumor activity in otherwise HR-proficient sensitive and resistant tumor cells.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Recombinasa Rad51/genética , Proteína p53 Supresora de Tumor/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Daño del ADN/efectos de los fármacos , Regulación hacia Abajo , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Furanos/farmacología , Furanos/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Recombinación Homóloga/efectos de los fármacos , Humanos , Imidazoles/farmacología , Imidazoles/uso terapéutico , Neoplasias/genética , Neoplasias/patología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/genética
16.
Cancer Sci ; 111(4): 1422-1434, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32011034

RESUMEN

Triple negative breast cancer (TNBC) displays higher heterogeneity, stronger invasiveness, higher risk of metastasis and poorer prognosis compared with major breast cancer subtypes. KIF3A, a member of the kinesin family of motor proteins, serves as a microtubule-directed motor subunit and has been found to regulate early development, ciliogenesis and tumorigenesis. To explore the expression, regulation and mechanism of KIF3A in TNBC, 3 TNBC cell lines, 98 cases of primary TNBC and paired adjacent tissues were examined. Immunohistochemistry, real-time PCR, western blot, flow cytometry, short hairpin RNA (shRNA) interference, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation techniques, transwell assays, scratch tests, and xenograft mice models were used. We found that KIF3A was overexpressed in TNBC and such high KIF3A expression was also associated with tumor recurrence and lymph node metastasis. Silencing of KIF3A suppressed TNBC cell proliferation by repressing the Rb-E2F signaling pathway and inhibited migration and invasion by repressing epithelial-mesenchymal transition. The tumor size was smaller and the number of lung metastatic nodules was lower in KIF3A depletion MDA-MB-231 cell xenograft mice than in the negative control group. In addition, KIF3A overexpression correlated with chemoresistance. These results suggested that high expression of KIF3A in TNBC was associated with the tumor progression and metastasis.


Asunto(s)
Factores de Transcripción E2F/genética , Cinesina/genética , Proteínas de Unión a Retinoblastoma/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/genética , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Cinesina/antagonistas & inhibidores , Ratones , Persona de Mediana Edad , Metástasis de la Neoplasia , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Cancer Sci ; 111(4): 1113-1123, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32012401

RESUMEN

Programmed cell death ligands (PD-Ls) are expressed in tumor cells where they bind to programmed cell death-1, an immunocyte co-receptor, resulting in tumor cell evasion from the immune system. Chemotherapeutic drugs have been recently reported to induce the expression of PD-L, such as PD-L1, in some cancer cells. However, little is known regarding PD-L2 expression and its role in oral squamous cell carcinoma (OSCC). In this study, we examined the effect of cisplatin on the expression and regulation of PD-L2 in OSCC cell lines and analyzed malignant behavior in PD-L2-expressing cells using colony, transwell and transformation assays. In addition, we examined PD-L2 expression in the tumor tissues of OSCC patients using cytology and tissue microarray methods. In OSCC cell lines, cisplatin treatment upregulated PD-L2 expression, along with that of the drug efflux transporter ABCG2, via signal transducers and activator of transcription (STAT) 1/3 activation. Moreover, PD-L2-positive or PD-L2-overexpressing cells demonstrated upregulation in both invasion and transformation ability but not in proliferation compared with PD-L2-negative or PD-L2-silencing cells. PD-L2 expression was also observed in OSCC cells of cytology samples and tissue from OSCC patients. The intensity of PD-L2 expression was correlated with more malignant morphological features in the histological appearance and an invasive pattern. Our findings indicate that cisplatin-upregulated PD-L2 expression in OSCC via STAT1/3 activation and the expression of PD-L2 are likely to be associated with malignancy in OSCC. The PD-L2 expression in cisplatin-resistant OSCC cells may be a critical factor in prognosis of advanced OSCC patients.


Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Neoplasias de la Boca/tratamiento farmacológico , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Cisplatino/efectos adversos , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT3/genética , Análisis de Matrices Tisulares
18.
Nat Genet ; 52(2): 187-197, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31913353

RESUMEN

Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens to understand endocrine drug resistance, we discovered ARID1A and other SWI/SNF complex components as the factors most critically required for response to two classes of estrogen receptor-alpha (ER) antagonists. In this context, SWI/SNF-specific gene deletion resulted in drug resistance. Unexpectedly, ARID1A was also the top candidate in regard to response to the bromodomain and extraterminal domain inhibitor JQ1, but in the opposite direction, with loss of ARID1A sensitizing breast cancer cells to bromodomain and extraterminal domain inhibition. We show that ARID1A is a repressor that binds chromatin at ER cis-regulatory elements. However, ARID1A elicits repressive activity in an enhancer-specific, but forkhead box A1-dependent and active, ER-independent manner. Deletion of ARID1A resulted in loss of histone deacetylase 1 binding, increased histone 4 lysine acetylation and subsequent BRD4-driven transcription and growth. ARID1A mutations are more frequent in treatment-resistant disease, and our findings provide mechanistic insight into this process while revealing rational treatment strategies for these patients.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Histona Desacetilasa 1/metabolismo , Factores de Transcripción/metabolismo , Acetilación , Animales , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular/genética , Proliferación Celular , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/genética , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 3-alfa del Hepatocito/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Histona Desacetilasa 1/genética , Humanos , Células MCF-7 , Ratones Endogámicos NOD , Factores de Transcripción/genética , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Nat Commun ; 11(1): 449, 2020 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-31974379

RESUMEN

Chromosome arm aneuploidies (CAAs) are pervasive in cancers. However, how they affect cancer development, prognosis and treatment remains largely unknown. Here, we analyse CAA profiles of 23,427 tumours, identifying aspects of tumour evolution including probable orders in which CAAs occur and CAAs predicting tissue-specific metastasis. Both haematological and solid cancers initially gain chromosome arms, while only solid cancers subsequently preferentially lose multiple arms. 72 CAAs and 88 synergistically co-occurring CAA pairs multivariately predict good or poor survival for 58% of 6977 patients, with negligible impact of whole-genome doubling. Additionally, machine learning identifies 31 CAAs that robustly alter response to 56 chemotherapeutic drugs across cell lines representing 17 cancer types. We also uncover 1024 potential synthetic lethal pharmacogenomic interactions. Notably, in predicting drug response, CAAs substantially outperform  mutations and focal deletions/amplifications combined. Thus, CAAs predict cancer prognosis, shape tumour evolution, metastasis and drug response, and may advance precision oncology.


Asunto(s)
Aneuploidia , Cromosomas Humanos , Resistencia a Antineoplásicos/genética , Tasa de Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Línea Celular Tumoral , Humanos , Estimación de Kaplan-Meier , Aprendizaje Automático , Modelos Biológicos , Neoplasias/mortalidad , Neoplasias/patología , Pronóstico , Procesos Estocásticos
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