Cancer-associated fibroblasts confer cisplatin resistance of tongue cancer via autophagy activation
Cancer-associated fibroblasts confer cisplatin resistance of tongue cancer via autophagy activation
复制标题
癌症相关成纤维细胞通过自噬激活赋予舌癌顺铂耐药性
DOI：
10.1016/j.biopha.2017.11.024
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发表时间：
2018-01-01
影响因子：
7.5
通讯作者：
Chen, Wei-liang
中科院分区：
文献类型：
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作者：
Liao, Juan-kun;Zhou, Bin;Chen, Wei-liang
癌相关成纤维细胞（CAFs）在舌鳞状细胞癌（TSCC）的发生、发展中起重要作用。然而，CAF对TSCC化疗耐药性的影响在很大程度上仍不清楚。本研究通过培养配对的原代成纤维细胞和正常成纤维细胞，检测其在TSCC顺铂敏感性中的作用，以及自噬相关蛋白LC 3和Beclin 1的表达。在顺铂作用下，CAFs组的细胞存活率和IC 50显著高于NFs组，而凋亡率显著低于NFs组。同时，顺铂可增加与CAFs共培养的TSCC中LC 3-II和Beclin 1的表达。CQ可抑制顺铂诱导的自噬流的激活，使LC 3-II蛋白积聚，增加LC 3定位的点状分布。Beclin 1 siRNA也能降低顺铂诱导的自噬。CQ和Beclin 1 siRNA均增加顺铂诱导的细胞凋亡，但抑制与CAFs共培养的TSCC的活力。在体内，顺铂和CQ的组合比单独顺铂显著抑制异种移植瘤的生长。总之，我们的研究结果强调了CAFs通过自噬激活在舌癌顺铂耐药中的重要作用，表明抑制自噬可能是TSCC化疗耐药的最佳策略。
Cancer-associated fibroblasts (CAFs) play important roles in carcinogenesis and progression of tongue squamous cell carcinoma (TSCC). However, effect of CAFs on chemotherapy resistance of TSCC remains largely obscure. Here, we cultured the matched primary CAFs and normal fibroblasts (NFs) pairs and detected their roles in cisplatin sensitivity of TSCC, as well as autophagy-related protein LC3 and Beclin1 expressions. During exposure to cisplatin, TSCC with CAFs group exhibited significantly increased cell viability and IC50, but reduced apoptosis than that with NFs group. Meanwhile, cisplatin increased the LC3-II and Beclin1 levels of those TSCC co-cultured with CAFs. Activation of cisplatin-induced autophagic flux was inhibited by CQ, which can accumulate LC3-II protein and increase punctate distribution of LC3 localization. Beclin1 siRNA also decreased the cisplatin-induced autophagy. Both CQ and Beclin1 siRNA increased cisplatin-induced apoptosis but inhibited viability of TSCC co-cultured with CAFs. In vivo, combination of cisplatin and CQ significantly inhibited the growth of xenografted tumors than cisplatin alone. Taken together, our findings highlight the important role of CAFs in cisplatin resistance of tongue cancer via autophagy activation, suggesting that inhibition of autophagy could be an optimal strategy for chemoresistance of TSCC.