Division of Biomedical Sciences, Chang Gung University of Science and Technology, Taoyuan, Taiwan, ROC; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan, Taiwan, ROC.
Department of Obstetrics and Gynaecology, Chang Gung Memorial Hospital Linkou Medical Centre, Taoyuan, Taiwan, ROC.
Biochem Pharmacol. 2021 Apr;186:114456. doi: 10.1016/j.bcp.2021.114456. Epub 2021 Feb 6.
Ovarian cancer is poorly treatable due, at least in part, to induced drug resistance to taxol- and cisplatin-based chemotherapy. Recent studies showed that ectopic overexpression of toll-like receptor 4 (TLR4) in ovarian cancer cells leads to upregulation of the androgen receptor (AR) and transactivation of taxol resistance genes, thereby causing chemoresistance. In the present study, we examined the signaling pathways involving TLR4 and interleukin 6 (IL-6) that enhance AR expression. Based on transcriptomic analysis, we show that IL-6 functions as a hub gene among the upregulated genes in taxol-treated TLR4-overexpressing ovarian cancer cells. Both the TLR4 activator taxol and IL-6 can induce AKT phosphorylation, whereas TLR4 knockdown or inhibition of the IL-6 signal transducer GP130 abrogates AKT activation. Furthermore, expression of AR and IL-6 is downregulated in TLR4-knockdown, taxol-resistant cells. In addition, TLR4 knockdown inhibits GP130 and IL-6 receptor alpha (IL6Rα) activities, indicating that TLR4 plays a critical role in IL-6 signaling. On the other hand, nuclear translocation of AR is induced by IL-6 treatment, whereas knockdown of endogenous IL-6 reduces AR and TLR4 expression in taxol-resistant ovarian cancer cells. These results indicate that TLR4 and IL-6 play a crucial role in AR gene regulation and function. We also identify interferon regulatory factor 1 (IRF1) as a downstream target of IL-6 signaling and as a regulator of AR expression. Moreover, analysis of clinical samples indicates that high IL-6 expression correlates with poor progression-free survival in ovarian cancer patients treated with taxol. Overall, our findings indicate that the TLR4/IL-6/IRF1 signaling axis represents a potential therapeutic target to overcome AR-based taxol resistance in ovarian cancer.
卵巢癌的治疗效果较差，至少部分原因是紫杉醇和顺铂化疗诱导的耐药性。最近的研究表明，卵巢癌细胞中 Toll 样受体 4（TLR4）的异位过表达导致雄激素受体（AR）的上调和紫杉醇耐药基因的转激活，从而导致化疗耐药。在本研究中，我们研究了涉及 TLR4 和白细胞介素 6（IL-6）的信号通路，这些通路增强了 AR 的表达。基于转录组分析，我们表明 IL-6 是紫杉醇处理的 TLR4 过表达卵巢癌细胞中上调基因的枢纽基因。TLR4 激动剂紫杉醇和 IL-6 均可诱导 AKT 磷酸化，而 TLR4 敲低或 IL-6 信号转导物 GP130 的抑制作用则消除了 AKT 的激活。此外，TLR4 敲低会下调紫杉醇耐药细胞中的 AR 和 IL-6 表达。此外，TLR4 敲低抑制了 GP130 和 IL-6 受体 alpha（IL6Rα）的活性，表明 TLR4 在 IL-6 信号中起着关键作用。另一方面，IL-6 处理诱导 AR 的核转位，而内源性 IL-6 的敲低则降低了紫杉醇耐药卵巢癌细胞中的 AR 和 TLR4 表达。这些结果表明 TLR4 和 IL-6 在 AR 基因调控和功能中起关键作用。我们还确定干扰素调节因子 1（IRF1）是 IL-6 信号的下游靶标，也是 AR 表达的调节剂。此外，对临床样本的分析表明，高 IL-6 表达与接受紫杉醇治疗的卵巢癌患者的无进展生存期较差相关。总体而言，我们的发现表明 TLR4/IL-6/IRF1 信号轴代表了克服卵巢癌中基于 AR 的紫杉醇耐药性的潜在治疗靶标。
