[Ethanol promotes oxaliplatin resistance in colorectal cancer by activating the TGF‑β/Smad/P21 signaling axis].

OBJECTIVES

To investigate the effect of ethanol for promoting oxaliplatin resistance in colorectal cancer (CRC) and the underlying molecular mechanisms.

METHODS

Lifetime alcohol consumption data from the PLCO cohort were analyzed to assess the association between alcohol drinking and CRC risk. The differential expressions of alcohol metabolism-related genes between CRC and normal tissues and their associations with recurrence and survival in chemotherapy-treated patients were analyzed based on GEO datasets. Fecal samples from healthy non-drinkers and CRC patients were collected for detecting ethanol levels using gas chromatography-mass spectrometry (GC-MS). In a mouse model bearing subcutaneous CRC xenograft treated with oxaliplatin, the effects of continuous ethanol exposure using the Lieber-DeCarli liquid diet and 4-methylpyrazole (4-MP) treatment on tumor growth were evaluated. In cultured SW480 and HCT116 cells, the effect of 100 and 200 mg/dL ethanol on oxaliplatin sensitivity, apoptosis, cell cycle distribution, and TGF‑β/Smad/P21/Rb axis proteins were analyzed, and the results were further validated with pirfenidone intervention experiment.

RESULTS

High-frequency drinkers had a significantly increased risk of CRC. ADH1B and ADH1C were significantly downregulated in CRC tissues, and their low expressions were associated with a higher recurrence rate and poorer overall survival in chemotherapy-treated patients. Ethanol was detected in fecal samples from both healthy individuals and CRC patients. In oxaliplatin-treated tumor-bearing mice, alcohol exposure resulted in a greater tumor volume. In SW480 and HCT116 cells, ethanol significantly increased oxaliplatin IC₅₀, reduced cell apoptosis, induced G0/G1 arrest, decreased S-phase fraction, and upregulated TGF-β1, p-Smad2, and P21 while downregulating p-Rb expression. Pirfenidone partially reversed these changes and attenuated drug resistance of the cells.

CONCLUSIONS

Ethanol accumulation activates the TGF-β/Smad/P21 axis to induce cell cycle arrest and promote oxaliplatin resistance in CRC cells, which can be partially reversed by pirfenidone inhibition.