Studying ethanol stress responses to better understand the association between alcohol and cancer

Alcohol consumption has been causally linked to at least 7 different types of cancer, including cancers of the oral cavity, esophagus, and liver. Tissues that come in direct contact with alcoholic beverages are particularly at risk for developing ethanol-related tumors. Despite the clear causal relationship, the exact molecular mechanisms underlying the carcinogenic effect of ethanol are not fully elucidated yet. 

In that respect, our research focuses on understanding how ethanol damages eukaryotic cells. With this project, we want to help prevent ethanol-induced cancers in the future by increasing awareness and by better advice on alcohol consumption.
We used in vitro human cell culture model as it allowed us to study the effects of ethanol in a highly controlled environment. We used multiple cell lines including healthy immortalized epithelial-like cells as well as oral cancer cell lines. Firstly, we observed that nontoxic ethanol concentrations were cell-line dependent and were much lower compared to the ethanol content of alcoholic beverages. Secondly, ethanol stress significantly inhibited cell proliferation by inducing a G1 cell cycle phase delay. Thirdly, we noticed that acute ethanol exposure induced replication stress, similarly as we discovered in our study in Saccharomyces cerevisiae. Replication stress can be caused by DNA damage. DNA damage can be induced by acetaldehyde, which is a highly reactive metabolite of ethanol. However, transient gene knockdown of ethanol-metabolizing genes, which should limit cellular acetaldehyde formation, did not alter our phenotype. Hence, we hypothesized that acetaldehyde might not be the only mechanism whereby ethanol can induce replication stress. Lastly, we performed a genome-wide transcriptomic analysis to get more insight into the molecular pathways that are affected by ethanol. Interestingly, ethanol-stressed cells significantly upregulated the several proteins involved in the Wnt signaling pathway. This pathway is an important regulator of cell proliferation and migration and dysregulation of Wnt signaling has been associated with increased malignant transformation and tumor metastasis.
In conclusion, our data indicated that ethanol exposure results in replication stress in eukaryotic cells. Replication fork stalling can induce genomic instability which is a hallmark of cancer. Additionally, we observed that ethanol enhanced Wnt signaling in human cells which can promote cell migration and metastasis


Lore Hoes (1,2,3) Karin Voordeckers (1,2) Rüveyda Dok (3) Sandra Nuyts (3,4) Kevin Verstrepen (1,2)


(1) Laboratory for Systems Biology, VIB-KU Leuven Center for Microbiology, 3000 Leuven, Belgium (2) Laboratory of Genetics and Genomics, Centre for Microbial and Plant Genetics, KU Leuven, 3000 Leuven, Belgium (3) Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, 3000 Leuven, Belgium (4) Department of Radiation Oncology, Leuven Cancer Institute, University Hospital Leuven

Presenting author

Lore Hoes, PhD Student, KU Leuven
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