Department of Urology, University of California at Davis, Sacramento, California.
Prostate. 2014 Feb;74(2):201-9. doi: 10.1002/pros.22741. Epub 2013 Oct 16.
Use of enzalutamide has improved the treatment of advanced prostate cancer. However, resistance to enzalutamide can develop frequently in initial responders. This study aimed to test whether overexpression of IL-6 and constitutive activation of Stat3 in prostate cancer cells increase resistance to enzalutamide.
Sensitivity of prostate cancer cells to enzalutamide was tested using cell growth assays and clonogenic assays. Quantitative reverse transcription-PCR, ELISA, and Western blotting were performed to detect expression levels of IL-6, c-Myc, survivin, and AR. Expression of Stat3 was downregulated using siRNA specific to Stat3. ChIP assay was performed to examine recruitment of AR to the PSA promoter.
Prostate cancer cells expressing autocrine IL-6 are resistant to enzalutamide and autocrine IL-6 leads to constitutive activation of Stat3 and its target genes. Down regulation of Stat3 led to an increase in sensitivity of prostate cancer cells to enzalutamide. Overexpression of constitutively active Stat3 in prostate cancer cells induced resistance to enzalutamide treatment. Constitutively active Stat3 also enhanced the recruitment of AR to PSA promoter which could not be disrupted by enzalutamide. The Stat3 inhibitor AG490 reversed enzalutamide resistance in prostate cancer cells, while combination treatment with enzalutamide and AG490 significantly inhibited cell growth and induced cell apoptosis.
This study demonstrates that the autocrine IL-6 pathway induces enzalutamide resistance in prostate cancer cells via the constitutive activation of Stat3. Co-targeting IL6-Stat3 pathway with enzalutamide may be utilized for treatment of advanced prostate cancer.
恩扎卢胺的使用改善了晚期前列腺癌的治疗效果。然而，在初始应答者中，恩扎卢胺的耐药性经常会发展。本研究旨在测试前列腺癌细胞中 IL-6 的过表达和 Stat3 的组成性激活是否会增加对恩扎卢胺的耐药性。
使用细胞生长测定法和集落形成测定法测试前列腺癌细胞对恩扎卢胺的敏感性。进行定量逆转录-PCR、ELISA 和 Western blot 以检测 IL-6、c-Myc、survivin 和 AR 的表达水平。使用特异性针对 Stat3 的 siRNA 下调 Stat3 的表达。进行 ChIP 测定以检查 AR 向 PSA 启动子的募集。
表达自分泌 IL-6 的前列腺癌细胞对恩扎卢胺具有耐药性，自分泌 IL-6 导致 Stat3 的组成性激活及其靶基因。Stat3 的下调导致前列腺癌细胞对恩扎卢胺的敏感性增加。在前列腺癌细胞中过表达组成性激活的 Stat3 会诱导对恩扎卢胺治疗的耐药性。组成性激活的 Stat3 还增强了 AR 向 PSA 启动子的募集，而恩扎卢胺无法破坏这种募集。Stat3 抑制剂 AG490 逆转了前列腺癌细胞中的恩扎卢胺耐药性，而恩扎卢胺和 AG490 的联合治疗显著抑制了细胞生长并诱导了细胞凋亡。
本研究表明，自分泌 IL-6 途径通过 Stat3 的组成性激活诱导前列腺癌细胞对恩扎卢胺产生耐药性。与恩扎卢胺联合靶向 IL6-Stat3 通路可能用于治疗晚期前列腺癌。
