CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer.
CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer.
复制标题
CCL2-SQSTM1 正反馈环抑制自噬，促进胃癌化疗耐药。
DOI：
10.7150/ijbs.25349
复制
发表时间：
2018
影响因子：
9.2
通讯作者：
Jin H
中科院分区：
文献类型：
--
作者：
Xu W;Wei Q;Han M;Zhou B;Wang H;Zhang J;Wang Q;Sun J;Feng L;Wang S;Ye Y;Wang X;Zhou J;Jin H
化疗是治疗各种癌症的最重要方法之一。然而，肿瘤细胞经常对化疗药物产生耐药性。近年来发现，免疫细胞分泌的多种细胞因子重建的肿瘤微环境在影响肿瘤细胞的治疗反应中起重要作用。在此，我们报道了肿瘤细胞可以分泌自分泌细胞因子，通过灭活促凋亡自噬来赋予化疗耐药性。通过细胞因子筛选，我们发现耐药癌细胞比药物敏感细胞分泌更多的CCL 2。这种分泌的CCL 2不仅可以维持耐药癌细胞的化学抗性，而且可以赋予药物敏感癌细胞耐药性。CCL 2通过激活PI 3 K-Akt-mTOR信号传导抑制促凋亡自噬和增加SQSTM 1表达来减弱药物诱导的细胞毒性。CCL 2在原发癌组织中的表达与SQSTM 1的表达也有很好的相关性。CCL 2敲低或自噬诱导成功逆转了肿瘤细胞的耐药性。此外，SQSTM 1的表达增加反过来又通过NF-κB信号通路激活CCL 2的转录，代表了维持耐药性的正反馈回路。因此，我们的研究结果为了解耐药性提供了新的见解，并表明CCL 2作为化疗耐药的生物标志物和干预靶点的潜在价值。
Chemotherapy is one of the most important approaches for the treatment of various cancers. However, tumor cells often develop resistance to chemotherapeutic drugs. The tumor microenvironment reconstituted by various cytokines secreted from immune cells was recently found to play important roles in affecting therapeutic response of tumor cells. Herein, we reported that tumor cells can secrete autocrine cytokines to confer chemoresistance by inactivating proapoptotic autophagy. Through cytokine screening, we found that drug resistant cancer cells secreted more CCL2 than drug sensitive cells. Such secreted CCL2 could not only maintain chemoresistance in drug-resistant cancer cells but also confer drug resistance to drug-sensitive cancer cells. CCL2 attenuated drug-induced cytotoxicity by activating PI3K-Akt-mTOR signaling to inhibit proapoptotic autophagy and increase SQSTM1 expression. CCL2 expression in primary carcinoma tissues also correlated well with SQSTM1 expression. Either CCL2 knock-down or autophagy induction successfully reversed drug resistance of tumor cells. Moreover, increased expression of SQSTM1 in turn activated CCL2 transcription via NF-κB signal pathway, representing a positive feedback loop to maintain drug resistance. Therefore, our results provided a new insight to understand drug resistance, and indicated the potential value of CCL2 as a biomarker and intervention target for chemotherapy resistance.
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影响因子：
64.5
作者：
Moscat, Jorge;Karin, Michael;Diaz-Meco, Maria T.
通讯作者：
Diaz-Meco, Maria T.
影响因子：
50.3
作者：
Duran, Angeles;Linares, Juan F.;Moscat, Jorge
通讯作者：
Moscat, Jorge
影响因子：
64.5
作者：
Green DR;Levine B
通讯作者：
Levine B
影响因子：
13.3
作者：
Kaminskyy, Vitaliy O.;Piskunova, Tatiana;Zhivotovsky, Boris
通讯作者：
Zhivotovsky, Boris
影响因子：
13.3
作者：
Dalby KN;Tekedereli I;Lopez-Berestein G;Ozpolat B
通讯作者：
Ozpolat B