恩扎鲁胺
前列腺癌
癌症研究
生物
SOX2
雄激素受体
LNCaP公司
波形蛋白
前列腺
癌症
癌细胞
TMPRS2型
转录因子
内科学
医学
免疫组织化学
免疫学
基因
遗传学
疾病
2019年冠状病毒病(COVID-19)
传染病(医学专业)
作者
Jitender Monga,Indra Adrianto,Craig Rogers,Shirish M. Gadgeel,Dhananjay Chitale,Joshi J. Alumkal,Himisha Beltran,Amina Zoubeidi,J. J. Ghosh
标识
DOI:10.1016/j.jbc.2021.101556
摘要
Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2). Inhibition of TRIB2 decreases the viability of enzalutamide-resistant prostate cancer cells, suggesting a critical role of TRIB2 in these cells. Moreover, the overexpression of TRIB2 confers resistance in prostate cancer cells to clinically relevant doses of enzalutamide, and this resistance is lost upon inhibition of TRIB2. Interestingly, we found that TRIB2 downregulates the luminal markers androgen receptor and cytokeratin 8 in prostate cancer cells but upregulates the neuronal transcription factor BRN2 (Brain-2) and the stemness factor SOX2 (SRY-box 2) to induce neuroendocrine characteristics. Finally, we show that inhibition of either TRIB2 or its downstream targets, BRN2 or SOX2, resensitizes resistant prostate cancer cells to enzalutamide. Thus, TRIB2 emerges as a potential new regulator of transdifferentiation that confers enzalutamide resistance in prostate cancer cells via a mechanism involving increased cellular plasticity and lineage switching.
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