Alcohol Consumption Promotes Colorectal Carcinoma Metastasis Via a CCL5-induced and AMPK-pathway-mediated Activation of Autophagy

There is a definite relationship between alcohol consumption and colorectal cancer (CRC) development. We investigated effect of alcohol consumption on CRC patients' progression and prognosis by utilizing epidemiological data and found patients with alcohol consumption increased risks of tumor-node-metastasis (TNM), organ metastasis and poorer prognosis. Because their tumor tissues displayed increased expression of C-C chemokine ligand 5 (CCL5), we hypothesized CCL5 might participate in cancer progression in such patients. Ethanol increased the secretion of CCL5 in two CRC cell lines, HT29 and DLD-1. Treatment with CCL5 directly increased migratory ability of these cells, whereas neutralization or knockdown of CCL5 can partially block alcohol-stimulated migration. We further investigated underlying mechanism of CCL5-induced migration. Our results indicated that effects of CCL5 on migration are mediated by the ability of CCL5 to induce autophagy, a cellular process known to be critical for migration. Using high-throughput sequencing and western blotting, we found induction of autophagy by CCL5 takes place via AMPK pathway. Aforementioned ethanol increases CCL5 secretion, CCL5 activates autophagy through AMPK pathway, and autophagy increases migration was confirmed by experiments with autophagy or AMPK inhibitors. To sum up, our study demonstrates that chronic alcohol consumption may promote metastasis of CRC through CCL5-induced autophagy.