Effects of curcumin on 5-fluorouracil resistance of colon cancer cells through the PI3K/AKT/mTOR pathway via MACC1

Abstract

: Colon cancer (CC) represents a common malignancy of the digestive tract featured by high metastasis and recurrence rates. Despite the critical role of 5-fluorouracil (5-Fu) in tumor therapy, long-term and heavy use of 5-Fu leads to reduced treatment efficacy in CC patients. Curcumin can avert multidrug resistance as a sensitizing agent. This study sought to investigate the mechanism of curcumin in 5-Fu resistance of CC cells. : Firstly, the LoVo/5-Fu CC cell line was constructed using gradient 5-Fu, and subjected to treatment with curcumin or oe-MACC1 and pathway inhibitor BEZ235. Cell proliferation was assessed by MTT and clone formation assays, and IC50 values were calculated. Cell apoptosis was evaluated by means of Annexin V-FITC/PI double staining. Levels of drug-resistance factors and Vimentin and E-cadherin were measured using RT-qPCR. Levels of PI3K/AKT/mTOR pathway-associated proteins were determined with a Western blot assay. : LoVo/5-Fu cells presented with increased IC50 value, enhanced proliferation, weakened apoptosis, augmented levels of drug-resistance factors and Vimentin, and diminished E-cadherin levels. MACC1 was highly-expressed and the PI3K/AKT/mTOR-pathway-associated proteins phosphorylated in LoVo/5-Fu cells. Curcumin partly averted 5-Fu resistance and decreased the ratios of p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR. MACC1 over-expression mitigated the action of curcumin on inhibiting 5-Fu resistance and elevating phosphorylation levels of PI3K/AKT/mTOR proteins. BEZ235 treatment abolished the action of over-expression of MACC1 on 5-Fu resistance of CC cells. : Our findings highlighted that curcumin suppressed the epithelial-mesenchymal transition of CC cells and thus reduced 5-Fu resistance of CC cells by regulating the PI3K/AKT/mTOR pathway via MACC1.