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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.

CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer