期刊
MOLECULAR CANCER THERAPEUTICS
卷 14, 期 8, 页码 1884-1895出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-14-1057
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资金
- U.S. Department of Veterans Affairs
- ORDVA Merits [I01 BX000526]
- Stand Up To Cancer-Prostate Cancer Foundation-Prostate Dream Team Translational Cancer Research Grant [SU2C-AACR-PCF DT0812]
- Movember Foundation
- [NIH/NCI CA140468]
- [CA168601]
- [CA179970]
- [DOD PC100502]
- NATIONAL CANCER INSTITUTE [P30CA093373, R21CA179970, R01CA140468, R01CA168601] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX002653, I01BX000526] Funding Source: NIH RePORTER
Castration-resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling. Alternative splicing of the AR to generate constitutively active, ligand-independent variants is one of the principal mechanisms that promote the development of resistance to next-generation antiandrogens such as enzalutamide. Here, we demonstrate that the splicing factor heterogeneous nuclear RNA-binding protein A1 (hnRNPA1) plays a pivotal role in the generation of AR splice variants such as AR-V7. hnRNPA1 is overexpressed in prostate tumors compared with benign prostates, and its expression is regulated by NF-kappa B2/p52 and c-Myc. CRPC cells resistant to enzalutamide exhibit higher levels of NF-kappa B2/p52, c-Myc, hnRNPA1, and AR-V7. Levels of hnRNPA1 and AR-V7 are positively correlated with each other in prostate cancer. The regulatory circuit involving NF-kappa B2/p52, c-Myc, and hnRNPA1 plays a central role in the generation of AR splice variants. Downregulation of hnRNPA1 and consequently of AR-V7 resensitizes enzalutamide-resistant cells to enzalutamide, indicating that enhanced expression of hnRNPA1 may confer resistance to AR-targeted therapies by promoting the generation of splice variants. These findings may provide a rationale for cotargeting these pathways to achieve better efficacy through AR blockade.
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