Characterization of Butyrate-Resistant Colorectal Cancer Cell Lines and the Cytotoxicity of Anticancer Drugs against These Cells.

Colorectal cancer (CRC) is the third most common cancer worldwide. The gut microbiota plays a critical role in homeostasis and carcinogenesis. Butyrate, a short-chain fatty acid produced by the gut microbiota, plays a role in intestinal homeostasis and acts as an anticancer agent by inhibiting growth and inducing apoptosis. However, microbiota studies have revealed an abnormally high abundance of butyrate-producing bacteria in patients with CRC and indicated that it leads to chemoresistance. We characterized butyrate resistance in HCT-116 and PMF-K014 CRC cells after treatment with a maximum butyrate concentration of 3.2 mM. The 50% inhibitory concentration of butyrate was increased in butyrate-resistant (BR) cells compared with that in parental (PT) cells. The mechanism of butyrate resistance was initially investigated by determining the expression of butyrate influx- and drug efflux-related genes. We found the increased expression of influx- and efflux-related genes in BR cells compared with that in PT cells. Proteomic data showed both identical and different proteins in PT and BR cells. Further analysis revealed the crossresistance of HCT-116 cells to metformin and oxaliplatin and that of PMF-K014 cells to 5-fluorouracil. Our findings suggest that the acquisition of butyrate resistance induces the development of chemoresistance in CRC cells, which may play an important role in CRC development, treatment, and metastasis.