Cancer-associated fibroblasts (CAFs) promote tumor growth and progression, and increase drug resistance through several mechanisms. We have investigated the effect of CAFs on the p53 response to doxorubicin in prostate cancer cells. We show that CAFs produce interleukin-6 (IL-6), and that IL-6 attenuates p53 induction and upregulation of the pro-apoptotic p53 target Bax upon treatment with doxorubicin. This is associated with increased levels of MDM2 mRNA, Mdm2 protein bound to p53, and ubiquitinated p53. IL-6 also inhibited doxorubicin-induced cell death. Inhibition of JAK or STAT3 alleviated this effect, indicating that IL-6 attenuates p53 via the JAK/STAT signaling pathway. These results suggest that CAF-derived IL-6 plays an important role in protecting cancer cells from chemotherapy and that inhibition of IL-6 could have significant therapeutic value.

癌症相关成纤维细胞（CAF）促进肿瘤生长和进展，并通过多种机制增加耐药性。我们研究了 CAF 对前列腺癌细胞中 p53 对阿霉素反应的影响。我们发现，CAF 产生白细胞介素 6 (IL-6)，并且在阿霉素治疗后，IL-6 会减弱 p53 的诱导和促凋亡 p53 靶标 Bax 的上调。这与 MDM2 mRNA、与 p53 结合的 Mdm2 蛋白和泛素化 p53 水平增加有关。IL-6 还抑制阿霉素诱导的细胞死亡。JAK 或 STAT3 的抑制减轻了这种效应，表明 IL-6 通过 JAK/STAT 信号通路减弱 p53。这些结果表明，CAF 衍生的 IL-6 在保护癌细胞免受化疗中发挥重要作用，并且抑制 IL-6 可能具有显着的治疗价值。