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.
Highlights
While extremely diverse in origin and in the type of associated mutations, cancer cells share common features, including the ability to use diverse sources of energy for cell proliferation and the ability to escape cell death [1]
We showed that a low CHO diet resulted in AMPK activation and mTOR inhibition leading to eukaryotic elongation factor 2 inhibition, blocking protein translation elongation
Lymphoma-bearing mice were fed either ad libitum or in CR conditions, which consists in a 25% reduction of caloric intake, in accordance with our recent work [20], we showed that a global reduction of caloric intake by 25% for 5 days was sufficient to reduce the glycemia of the mice (Figure 1A) and to decrease Mcl-1 expression by 50%(Figure 1B, 1C)
Summary
While extremely diverse in origin and in the type of associated mutations, cancer cells share common features, including the ability to use diverse sources of energy for cell proliferation and the ability to escape cell death [1]. Further research established that the Warburg effect, observed in about 80% of cancers, is required for energy production and for the generation of macronutrients and the redox systems that are required for the rapid proliferation of cancer cells [3]. Since this discovery, researchers and pharmaceutical companies are developing ways to modulate metabolism in order to limit tumor appearance and/or enhance treatment. How food intake and how specific macronutrients impact on the response to chemotherapy is still largely unknown
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