Mechanisms Of Dichloroacetate Regulating Chemo-resistance Through AMPK/mTOR Signaling Pathway In Colon Cancer Cell

BACKGROUND AND OBJECTIVE: Chemo-resistance is a common problem in the treatment of colon cancer,which poses a serious threat to patients’ survival.DCA has been reported to promote chemotherapy in combined application with other drugs,however its effect on colon cancer is unknown.The mechanism of how DCA exert its anti-cancer effect needs for further study.miRNAs are widely involved in the regulation of signal transduction in tumor cells,while the relationship between miRNAs and chemo-sensitivity remains unknown.In this study,we demonstrated that DCA promoted chemo-sensitivity of colon cancer cells to oxaliplatin,screened miRNA molecules that influence the effect of DCA,and analyzed the biological function and mechanism of these miRNAs.METHODS: miRNAs with significant changes in colon cancer HCT116 cells treated with DCA were screened by microarray.The protein molecules associated with AMPK/mTOR pathway changed significantly after DCA treatment were screened by proteomics analysis.The sensitivity of colon cancer cells to oxaliplatin was determined after miRNAs’ expressions were changed.The relationship between miRNAs and CAB39 was confirmed by luciferase reporter assay.The effect of CAB39 on the chemo-sensitivity of colon cancer cells was determined by interfering with the expression of CAB39.The expression of CAB39 in normal epithelium and tumor tissues were analyzed by Oncomine database.RESULTS: miR-107 and miR-543 were down-regulated after DCA treatment.miR-107 and miR-543 could affect the activation of AMPK/mTOR pathway by targeting CAB39,thus improving the sensitivity of colon cancer cells to oxaliplatin.The expression of CAB39 in colon cancer was down-regulated compared to normal colonic epithelium.CONCLUSION: Our results suggest that DCA can affect chemo-sensitivity of colon cancer cells to oxaliplatin by influencing the activation of miR-107/543-CAB39-AMPK-mTOR pathway.