Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells
Interleukin-6 derived from cancer-associated fibroblasts attenuates the p53 response to doxorubicin in prostate cancer cells
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癌相关成纤维细胞来源的白介素6减弱前列腺癌细胞对阿霉素的P53反应
DOI：
10.1038/s41420-020-0272-5
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发表时间：
2020-06-02
影响因子：
7
通讯作者：
Wiman, Klas G.
中科院分区：
文献类型：
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作者：
Cheteh, Emarndeena H.;Sarne, Victoria;Wiman, Klas G.
癌症相关成纤维细胞（CAFs）通过多种机制促进肿瘤生长和进展，并增加耐药性。我们研究了cas对前列腺癌细胞中p53对阿霉素反应的影响。我们发现cas产生白细胞介素-6 (IL-6)， IL-6在阿霉素治疗后减弱p53诱导和促凋亡p53靶点Bax的上调。这与MDM2 mRNA、与p53结合的MDM2蛋白和泛素化p53水平升高有关。IL-6也能抑制阿霉素诱导的细胞死亡。抑制JAK或STAT3可减轻这种作用，表明IL-6通过JAK/STAT信号通路减弱p53。这些结果表明，cafa衍生的IL-6在保护癌细胞免受化疗的作用中起着重要作用，抑制IL-6可能具有重要的治疗价值。
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.