Submitted November 26, 2008
Accepted March 15, 2009
Alcohol consumption and decreased risk of non-Hodgkin's lymphoma: role of mTOR dysfunction
Patrick R. Hagner, Krystyna Mazan-Mamczarz, Bojie Dai, Sharon Corl, X. Frank Zhao, and Ronald B. Gartenhaus*
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, United States
* Corresponding author; email: rgartenhaus{at}som.umaryland.edu.
A number of epidemiologic studies to date support the emerging paradigm that current alcohol consumers have decreased risk of most types of non-Hodgkin's lymphoma. The observed lower risk among people who drank alcohol does not seem to vary with beverage type. The mechanisms accounting for alcohol-induced decrease in the incidence of lymphomas remain largely unknown. We demonstrate that low dose chronic exposure to ethanol inhibits mTORC1 complex formation resulting in decreased phosphorylation events involved in mTOR pathway signaling in a lymphoid-tissue specific manner. These changes in mTOR signaling lead to a decrease in eIF4E associated with the translation initiation complex and a repression of global cap-dependent synthesis in both lymphoma cell lines and normal donor lymphocytes. Significantly, we were able to show that chronic exposure of ethanol at physiologically relevant concentrations in a mouse xenograft model results in a striking inhibition of lymphoma growth. Our data support a paradigm in which chronic ethanol exposure inhibits mTOR signaling in lymphocytes with a significant repression of cap-dependent translation, reducing the tumorigenic capacity of NHL in a human xenograft model. The ethanol-mediated repression of mTOR signaling coupled with decreased in vivo lymphoma growth underscore the critical role of mTOR signaling and translation in lymphoma.
