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

Abstract

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.

KSHV dysregulates bulk macroautophagy, mitophagy and UPR to promote endothelial to mesenchymal transition and CCL2 release, key events in viral‐driven sarcomagenesis

“…42 Interestingly, KSHV is able to infect macrophages 43 Given that macrophages are the most representative leukocytes in KS lesions, the finding that KSHV adopts several strategies to skew their polarization into M2 elucidates a crucial event in viral-induced tumorigenesis. Furthermore, CCL2 may negatively regulate autophagy 18 or engage a cross-talk with SQSTM1 in which CCL2 activates MTOR and reduces autophagy, leading to an accumulation of SQSTM1 that promotes CCL2 transcription, 19 in a positive feedback loop essential for the angiogenesis and EndMT reprogramming necessary for KSHV-driven sarcomagenesis. Also SQSTM1 may upregulate the expression of SNAI1 33,44 and inhibit the degradation of TWIST1, another transcription factor that drives EMT.…”

Fusobacterium nucleatum Promotes Gastric Cancer Aggressiveness through Upregulation of Cell Mobility and Interferon Genes

“…4C). CCL2 is a chemoattractant of macrophages, and upregulation of CCL2 is shown to promote cancer progression [21,33]. Since both low and high MOI treatments induce the expression of CCL2 with similar strength, this suggests that the activation of CCL2 by Fusobacterium nucleatum infection is possibly done through an independent mechanism.…”

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

“…Future studies will be required to evaluate the inflammatory response across racially divergent breast cancer cell lines or tissues. What we do know, however, is that compounds like apigenin that attenuate the CCL2/CCR2 axis would slow the aggressive nature of TNBC and hormone positive breast cancers (27,28) by attenuating invasion, metastasis, EMT and the development of drug resistance (59)(60)(61)(62). CCL2 inhibitors have been tested in various tumors, tumor cells and xenograft models with CCL2 lowering effects brought about by losartan (63) anlotinib (64) imatinib (65) zoledronic acid (66) oroxylin A (67) aspirin (68) natural compounds in coffee (kahweol acetate, cafestol) (69) or conophylline from Ervatamia microphylla (70) which can reduce invasive inflammatory tumor infiltration.…”