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1.
Cancer Res ; 81(8): 2044-2055, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33574092

RESUMO

Wnt signaling is a major driver of stemness and chemoresistance in ovarian cancer, yet the genetic drivers that stimulate its expression remain largely unknown. Unlike other cancers, mutations in the Wnt pathway are not reported in high-grade serous ovarian cancer (HGSOC). Hence, a key challenge that must be addressed to develop effective targeted therapies is to identify nonmutational drivers of Wnt activation. Using an miRNA sensor-based approach, we have identified miR-181a as a novel driver of Wnt/ß-catenin signaling. miR-181ahigh primary HGSOC cells exhibited increased Wnt/ß-catenin signaling, which was associated with increased stem-cell frequency and platinum resistance. Consistent with these findings, inhibition of ß-catenin decreased stem-like properties in miR-181ahigh cell populations and downregulated miR-181a. The Wnt inhibitor SFRP4 was identified as a novel target of miR-181a. Overall, our results demonstrate that miR-181a is a nonmutational activator of Wnt signaling that drives stemness and chemoresistance in HGSOC, suggesting that the miR-181a-SFRP4 axis can be evaluated as a novel biomarker for ß-catenin-targeted therapy in this disease. SIGNIFICANCE: These results demonstrate that miR-181a is an activator of Wnt signaling that drives stemness and chemoresistance in HGSOC and may be targeted therapeutically in recurrent disease.


Assuntos
MicroRNAs/fisiologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas/fisiologia , Via de Sinalização Wnt/fisiologia , Animais , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Camundongos , MicroRNAs/metabolismo , Terapia de Alvo Molecular , Mutação , Gradação de Tumores , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas/genética , Células Tumorais Cultivadas , Via de Sinalização Wnt/genética , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
2.
Clin Cancer Res ; 24(18): 4588-4601, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29653924

RESUMO

Purpose: Acquired resistance to cisplatin is a major barrier to success in treatment of various cancers, and understanding mitotic mechanisms unique to cisplatin-resistant cancer cells can provide the basis for developing novel mitotic targeted therapies aimed at eradicating these cells.Experimental Design: Using cisplatin-resistant models derived from primary patient epithelial ovarian cancer (EOC) cells, we have explored the status of mitotic exit mechanisms in cisplatin-resistant cells.Results: We have uncovered an unexpected role of long-term cisplatin treatment in inducing mitotic exit vulnerability characterized by increased spindle checkpoint activity and functional dependency on Polo-like kinase 1 (PLK1) for mitotic exit in the presence of anaphase promoting complex/cyclosome (APC/C) dysfunction in a cisplatin-resistant state. Accordingly, PLK1 inhibition decreased the survival of cisplatin-resistant cells in vitro and in vivo and exacerbated spindle checkpoint response in these cells. APC/CCDC20 inhibition increased sensitivity to pharmacologic PLK1 inhibition, further confirming the existence of APC/C dysfunction in cisplatin-resistant cells. In addition, we uncovered that resistance to volasertib, PLK1 inhibitor, is due to maintenance of cells with low PLK1 expression. Accordingly, stable PLK1 downregulation in cisplatin-resistant cells induced tolerance to volasertib.Conclusions: We provide the first evidence of APC/C dysfunction in cisplatin-resistant state, suggesting that understanding APC/C functions in cisplatin-resistant state could provide a basis for developing novel mitotic exit-based therapies to eradicate cisplatin-resistant cancer cells. Our results also show that PLK1 downregulation could underlie emergence of resistance to PLK1-targeted therapies in cancers. Clin Cancer Res; 24(18); 4588-601. ©2018 AACR.


Assuntos
Ciclossomo-Complexo Promotor de Anáfase/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Proteínas de Ciclo Celular/genética , Cisplatino/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Ciclossomo-Complexo Promotor de Anáfase/efeitos dos fármacos , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mitose/efeitos dos fármacos , Quinase 1 Polo-Like
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