Prostate cancer (PCa) is a malignant tumor with an extremely high prevalence. Doxorubicin is the first‐line clinical treatment for castration‐resistant PCa. Clinically, relapse is almost inevitable due to the cancer cells' increasing resistance to doxorubicin. Our previous studies have revealed that retinoic acid‐related orphan nuclear receptor γ (RORγ) is a key protein for cancer progression and a promising target for PCa therapy. Though, RORγ's role and mechanism in doxorubicin‐resistant PCa remain unclear. To study the mechanism of doxorubicin resistance, we generated a doxorubicin‐resistant PCa cell line C4‐2B (C4‐2B DoxR) in this study, by culturing cells in an increasing doxorubicin concentration. Here, we show that RORγ expression was upregulated in C4‐2B DoxR cells compared with that in normal C4‐2B cells. The RORγ‐stably‐overexpressing PCa cell line constructed by lentiviral transfection showed an obvious improvement in doxorubicin resistance and a trend toward castration resistance. Furthermore, RORγ‐specific small molecule inhibitors XY018, GSK805, and SR2211 can significantly inhibit the proliferation of C4‐2B DoxR cells and promote their apoptosis. Collectively, these results have demonstrated the correlation between the upregulation of RORγ and the development of PCa's doxorubicin resistance, thus providing new ideas for solving the problem of chemotherapy drug resistance in PCa.

中文翻译：

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孤儿核受体 RORγ 在前列腺癌中赋予阿霉素耐药性。

前列腺癌（PCa）是一种发病率极高的恶性肿瘤。阿霉素是去势抵抗性前列腺癌的一线临床治疗。临床上，由于癌细胞对多柔比星的抵抗力增加，复发几乎是不可避免的。我们之前的研究表明，视黄酸相关孤儿核受体 γ（RORγ）是癌症进展的关键蛋白，也是 PCa 治疗的有希望的靶点。尽管如此，RORγ 在耐多柔比星 PCa 中的作用和机制仍不清楚。为了研究多柔比星耐药的机制，我们在本研究中通过在增加多柔比星浓度的情况下培养细胞，产生了多柔比星耐药的 PCa 细胞系 C4-2B (C4-2B DoxR)。在这里，我们表明与正常 C4-2B 细胞相比，C4-2B DoxR 细胞中的 RORγ 表达上调。通过慢病毒转染构建的 RORγ 稳定过表达 PCa 细胞系显示出阿霉素耐药性的明显改善和去势耐药性的趋势。此外，RORγ特异性小分子抑制剂XY018、GSK805和SR2211可显着抑制C4-2B DoxR细胞的增殖并促进其凋亡。总的来说，这些结果证明了RORγ的上调与PCa对阿霉素耐药的发展之间的相关性，从而为解决PCa化疗耐药问题提供了新的思路。SR2211 可显着抑制 C4-2B DoxR 细胞的增殖并促进其凋亡。总的来说，这些结果证明了RORγ的上调与PCa对阿霉素耐药的发展之间的相关性，从而为解决PCa化疗耐药问题提供了新的思路。SR2211 可显着抑制 C4-2B DoxR 细胞的增殖并促进其凋亡。总的来说，这些结果证明了RORγ的上调与PCa对阿霉素耐药的发展之间的相关性，从而为解决PCa化疗耐药问题提供了新的思路。