Alcohol consumption and decreased risk of non-Hodgkin lymphoma: role of mTOR dysfunction

Abstract

Several epidemiologic studies support the emerging paradigm that current alcohol consumers have decreased risk of most types of non-Hodgkin 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 mammalian target of rapamycin (mTOR) C1 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 capdependent synthesis in both lymphoma cell lines and normal donor lymphocytes. We show that chronic exposure of ethanol at physiologically relevant concentrations in a xenograft model results in a striking inhibition of lymphoma growth. IntroductionAlcohol abuse is associated with diseases of the liver, pancreas, and breast, and many other malignant disorders. 1,2 Interestingly, in contrast to solid tumors, several epidemiologic studies, including a large pooled analysis of case-control studies 3 and a recent cohort study, 4 indicate that persons who frequently consume small amounts of alcohol (1 or 2 drinks per day) have decreased risk of most types of non-Hodgkin lymphoma (NHL). The underlying biologic mechanism(s) for this negative association is (are) unknown at present.Ethanol decreases protein synthesis, and this effect is associated with changes in the phosphorylation status of several key components of the translational machinery. 5,6 Chronic alcohol intake is associated with disruption of the mammalian target of rapamycin (mTOR) signaling pathway; however, few mechanistic details are known about how ethanol interrupts this critical signaling pathway involved in translation. 7 mTOR forms 2 functionally distinct multiprotein serine/threonine kinase complexes, mTORC1 and mTORC2. The mTORC1 complex controls protein synthesis by phosphorylating key downstream effector molecules, the translational inhibitor protein 4E-BP1 and, p70 S6 kinase in response to sensory inputs, such as nutritional, growth factor, and cellular energy status. Activation of the p70 S6 kinase results in phosphorylation of the ribosomal protein S6 (RPS6) and allows its interaction with other ribosomal subunits and ribosomal biogenesis. 8 Phosphorylation of ribosomal protein S6 by p70 S6 kinase stimulates the translation of mRNAs with a 5Ј oligopyrimidine tract, which typically encode components of the protein synthesis machinery. 8 The signaling pathways that converge on mTOR are commonly activated in multiple human malignancies. The dysregulation of mTOR signaling leads to a selective increase in translation of messages that encode antiapoptotic proteins, activators of cell cycle progression, and growth factors, such as cyclin D1 and c-myc. 9,10 This underscores the importance of targeted inhibition of mTOR as...

Risk Factors for Multiple Myeloma: A Systematic Review of Meta-Analyses

“…The potential protective effects of alcohol consumption on MM risk 61 have been attributed to its immunomodulatory effects [72][73][74] or its inhibition through ethanol on the mammalian target of rapamycin signaling. 75 The special protective effects of wine seem in line with the respective pattern in cardiovascular disease prevention, 76 but the underlying mechanisms remain elusive.…”

Targeting the translational machinery as a novel treatment strategy for hematologic malignancies

“…Recently, the Gartenhaus laboratory has established a paradigm in which chronic ethanol exposure inhibits mTOR signaling in lymphocytes with a significant repression of cap-dependent translation and reduction in the tumorigenic capacity of NHL in a human lymphoma xenograft system. 63 The observed ethanol-mediated repression of mTOR signaling coupled with a decrease in lymphoma growth presented underscore the critical role of mTOR signaling and translation in lymphoma. 63 The role of rapamycin and its derivatives and their mechanism of action are still under investigation.…”

“…63 The observed ethanol-mediated repression of mTOR signaling coupled with a decrease in lymphoma growth presented underscore the critical role of mTOR signaling and translation in lymphoma. 63 The role of rapamycin and its derivatives and their mechanism of action are still under investigation. A recent report demonstrated that rapamycin treatment increased the cap-dependent translation of cervical carcinoma and embryonic kidney cells lines 33 illustrating how rapamycin can have cell type-specific effects.…”

Association of Alcohol Intake with the Risk of Malignant Lymphoma and Plasma Cell Myeloma in Japanese: A Population-Based Cohort Study (Japan Public Health Center–based Prospective Study)

“…However, we found that lymphoid neoplasm risk was strongly associated with relatively heavy alcohol consumption, ≥300 g/week, suggesting that the decreased risk may involve other mechanisms. Recently, inhibitory effect of ethanol on the mammalian target of rapamycin signaling was proposed as another possible mechanism (20). Exposure to ethanol was shown to dose-dependently inhibit the mammalian target of rapamycin pathway signaling in a lymphoid tissue-specific manner, and chronic exposure at physiologically relevant concentrations in a xenograft model resulted in the inhibition of lymphoma *P for trend was evaluated among current drinkers.…”