George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642; Department of Urology, Second Affiliated Hospital of Soochow University, Suzhou, 215004 China.
George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Wilmot Cancer Center. University of Rochester Medical Center, Rochester, New York 14642; Department of Urology, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, 310016 China.
J Biol Chem. 2013 Jun 7;288(23):16476-16483. doi: 10.1074/jbc.M112.448142. Epub 2013 Apr 22.
Prostate cancer (PCa) stem/progenitor cells are known to have higher chemoresistance than non-stem/progenitor cells, but the underlying molecular mechanism remains unclear. We found the expression of testicular nuclear receptor 4 (TR4) is significantly higher in PCa CD133(+) stem/progenitor cells compared with CD133(-) non-stem/progenitor cells. Knockdown of TR4 levels in the established PCa stem/progenitor cells and the CD133(+) population of the C4-2 PCa cell line with lentiviral TR4 siRNA led to increased drug sensitivity to the two commonly used chemotherapeutic drugs, docetaxel and etoposide, judging from significantly reduced IC50 values and increased apoptosis in the TR4 knockdown cells. Mechanism dissection studies found that suppression of TR4 in these stem/progenitor cells led to down-regulation of Oct4 expression, which, in turn, down-regulated the IL-1 receptor antagonist (IL1Ra) expression. Neutralization experiments via adding these molecules into the TR4 knockdown PCa stem/progenitor cells reversed the chemoresistance, suggesting that the TR4-Oct4-IL1Ra axis may play a critical role in the development of chemoresistance in the PCa stem/progenitor cells. Together, these studies suggest that targeting TR4 may alter chemoresistance of PCa stem/progenitor cells, and this finding provides the possibility of targeting TR4 as a new and better approach to overcome the chemoresistance problem in PCa therapeutics.
前列腺癌（PCa）干细胞/祖细胞被认为比非干细胞/祖细胞具有更高的化疗耐药性，但潜在的分子机制尚不清楚。我们发现睾丸核受体 4（TR4）在 PCa CD133(+)干细胞/祖细胞中的表达明显高于 CD133(-)非干细胞/祖细胞。用慢病毒 TR4 siRNA 敲低已建立的 PCa 干细胞/祖细胞和 C4-2 PCa 细胞系中的 CD133(+)群体中的 TR4 水平，导致对两种常用化疗药物多西他赛和依托泊苷的敏感性增加，从显著降低的 IC50 值和增加的 TR4 敲低细胞中的细胞凋亡可以看出。机制剖析研究发现，这些干细胞/祖细胞中 TR4 的抑制导致 Oct4 表达下调，进而导致白细胞介素 1 受体拮抗剂（IL1Ra）表达下调。通过向 TR4 敲低的 PCa 干细胞/祖细胞中添加这些分子进行中和实验，逆转了耐药性，表明 TR4-Oct4-IL1Ra 轴可能在 PCa 干细胞/祖细胞化疗耐药性的发展中起关键作用。总之，这些研究表明靶向 TR4 可能改变 PCa 干细胞/祖细胞的化疗耐药性，这一发现为靶向 TR4 作为克服 PCa 治疗中化疗耐药性问题的新方法提供了可能性。
