Ethanol-mediated stress promotes autophagic survival and aggressiveness of colon cancer cells via activation of Nrf2/HO-1 pathway

Antonella D'Anneo, Francesco Cappello, Marianna Lauricella, Antonella Marino Gammazza, Sonia Emanuele, Daniela Carlisi, Rosario Barone, Claudia Campanella, Cesare Cernigliaro, Giuseppe Calvaruso, Michela Giuliano, Claudia Campanella, Antonella Marino Gammazza, Rosario Barone, Alfio Distefano, Lucia Longhitano, Francesco Cappello

Research output: Contribution to journalArticle

9 Citations (Scopus)


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 differentcolon 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 promotesthe 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.
Original languageEnglish
Pages (from-to)505-
Number of pages21
Publication statusPublished - 2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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