Mesenchymal stem cells (MSCs) have been proved to drive castration resistant prostate cancer (CRPC). In this study, we aim to investigate the contribution of MSCs to the development of docetaxel resistance in CRPC cells and its potential mechanisms. The effect of MSCs on CRPC cells resistance to docetaxel was determined using in vivo and in vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses. MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel. These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy.

中文翻译：

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间充质干细胞通过诱导TGF-β1介导的细胞自噬使去势抵抗性前列腺癌对多西他赛化疗不敏感

间充质干细胞（MSCs）已被证明可驱动去势抵抗性前列腺癌（CRPC）。在这项研究中，我们旨在研究MSC对CRPC细胞中多西他赛耐药性发展的贡献及其潜在机制。使用体内和体外方法确定MSC对CRPC细胞对多西紫杉醇抗性的作用。CCK8和PI / Annexin V-FITC测定用于检查细胞活力和凋亡。通过酶联免疫吸附测定法测定转化生长因子-β1的浓度，并使用小干扰RNA进行功能分析。MSC显着降低了CRPC细胞对多西他赛诱导的体内和体外增殖抑制和细胞凋亡促进的敏感性。在多西他赛给药下与MSC共培养的CRPC细胞具有更高的自噬激活能力，而自噬抑制剂可有效逆转MSCs对多西他赛的耐药性。此外，在多西他赛给药下，MSCs诱导的CRPC细胞自噬的增加取决于分泌TGF-β1的MSC，抑制MSC中TGF-β1的分泌可能因此增加CRPC细胞对多西他赛的敏感性。这些结果表明，多西紫杉醇给药的CRPC细胞可能引起MSC分泌TGF-β1的增加，这使CRPC对多西紫杉醇化学疗法不敏感，通过诱导细胞自噬加速化学抗性的发生。多西他赛给药后，MSCs诱导的CRPC细胞自噬的增加取决于MSCs分泌TGF-β1，抑制MSCs中TGF-β1的分泌可能因此增加CRPC细胞对多西紫杉醇的敏感性。这些结果表明，多西紫杉醇给药的CRPC细胞可能引起MSC分泌TGF-β1的增加，这使CRPC对多西紫杉醇化学疗法不敏感，通过诱导细胞自噬加速化学抗性的发生。多西他赛给药后，MSCs诱导的CRPC细胞自噬的增加取决于MSCs分泌TGF-β1，抑制MSCs中TGF-β1的分泌可能因此增加CRPC细胞对多西紫杉醇的敏感性。这些结果表明，多西他赛给药的CRPC细胞可能引起MSC分泌TGF-β1的增加，这使CRPC对多西他赛化学疗法不敏感，通过诱导细胞自噬加速化学抗性的发生。