Abstract
Epidemiological studies suggest that chronic alcohol consumption is a lifestyle risk factor strongly associated with colorectal cancer development and progression. The aim of the present study was to examine the effect of ethanol (EtOH) on survival and progression of three different colon cancer cell lines (HCT116, HT29, and Caco-2). Our data showed that EtOH induces oxidative and endoplasmic reticulum (ER) stress, as demonstrated by reactive oxygen species (ROS) and ER stress markers Grp78, ATF6, PERK and, CHOP increase. Moreover, EtOH triggers an autophagic response which is accompanied by the upregulation of beclin, LC3-II, ATG7, and p62 proteins. The addition of the antioxidant N-acetylcysteine significantly prevents autophagy, suggesting that autophagy is triggered by oxidative stress as a prosurvival response. EtOH treatment also upregulates the antioxidant enzymes SOD, catalase, and heme oxygenase (HO-1) and promotes the nuclear translocation of both Nrf2 and HO-1. Interestingly, EtOH also upregulates the levels of matrix metalloproteases (MMP2 and MMP9) and VEGF. Nrf2 silencing or preventing HO-1 nuclear translocation by the protease inhibitor E64d abrogates the EtOH-induced increase in the antioxidant enzyme levels as well as the migration markers. Taken together, our results suggest that EtOH mediates both the activation of Nrf2 and HO-1 to sustain colon cancer cell survival, thus leading to the acquisition of a more aggressive phenotype.
Highlights
Colorectal cancer (CRC) is one of the most widespread cancers in the world [1]
The aim of the present research was to evaluate the role of nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 axis in promoting colon cancer survival and progression under ethanol stimulation
We examined the level of p62, a multifunctional protein considered as a marker of autophagic flux. p62 is localized to the autophagosome via light chain 3 (LC3) interaction and is constantly degraded by the autophagy–lysosome system [38]
Summary
Europe, and North America [2] This geographic variability has been linked to differences in environment and lifestyle [2]. Numerous risk factors have been correlated with the development of CRC, including genetic factors, inflammation, intestinal microflora composition, as well as harmful lifestyle habits, such as smoking, high consumption of red meats, and alcohol intake [3]. Chronic and heavy alcohol consumption, a common lifestyle habit of developed countries, has been associated with an increased risk of developing gastrointestinal cancers, including CRC [4,5]. The association between alcohol drinking and CRC is dose-dependent. In addition to act as a risk factor for carcinogenesis, many studies indicate that chronic alcohol consumption promotes colon tumor progression [6,7,8,9]
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