Low carbohydrate diet prevents Mcl-1-mediated resistance to BH3-mimetics

Abstract

Overexpression of Mcl-1 is implicated in resistance of several cancers to chemotherapeutic treatment, therefore identifying a safe way to decrease its expression in tumor cells represents a central goal. We investigated if a modulation of the diet could impact on Mcl-1 expression using a Myc-driven lymphoma model. We established that a partial reduction of caloric intake by 25% represents an efficient way to decrease Mcl-1 expression in tumor cells. Furthermore, using isocaloric custom diets, we observed that carbohydrates (CHO) are the main regulators of Mcl-1 expression within the food. Indeed, feeding lymphoma-bearing mice with a diet having 25% less carbohydrates was sufficient to decrease Mcl-1 expression by 50% in lymphoma cells. We showed that a low CHO diet resulted in AMPK activation and mTOR inhibition leading to eukaryotic elongation factor 2 (eEF2) inhibition, blocking protein translation elongation. Strikingly, a low CHO diet was sufficient to sensitize Myc-driven lymphoma-bearing mice to ABT-737-induced cell death in vivo. Thus reducing carbohydrate intake may represent a safe way to decrease Mcl-1 expression and to sensitize tumor cells to anti-cancer therapeutics.

Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance

“…Dietary restriction (DR) without malnutrition, which includes caloric restriction (CR) and fasting, is well recognized as one of the most reliable methods to enhance life span and reduce the incidence of a wide variety of diseases, including human cancers (Fontana and Partridge, 2015). DR has a beneficial impact on health and life span, affects cancer development (Longo and Mattson, 2014;Lu et al, 2017;Meynet and Ricci, 2014), and sensitizes tumor cells to chemotherapy (Meynet et al, 2013;Rubio-Patiñ o et al, 2016), notably by increasing tumor immunosurveillance (Di Biase et al, 2016). The identification of new methods to induce immunosurveillance has become crucial for the development of effective therapeutic protocols against cancers, the inhibition of tumor development and progression, and the enhancement of long-term protection.…”