mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells

Publication date: Available online 24 March 2016
Source:Cancer Cell
Author(s): Raju V. Pusapati, Anneleen Daemen, Catherine Wilson, Wendy Sandoval, Min Gao, Benjamin Haley, Andreas R. Baudy, Georgia Hatzivassiliou, Marie Evangelista, Jeff Settleman
Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. In various cancer cells exposed to a continuous glycolytic block, we identified a recurrent reprogramming mechanism involving sustained mTORC1 signaling that underlies escape from glycolytic addiction. Active mTORC1 directs increased glucose flux via the pentose phosphate pathway back into glycolysis, thereby circumventing a glycolysis block and ensuring adequate ATP and biomass production. Combined inhibition of glycolysis and mTORC1 signaling disrupted metabolic reprogramming in tumor cells and inhibited their growth in vitro and in vivo. These findings reveal novel combinatorial therapeutic strategies to realize the potential benefit from targeting the Warburg effect.

Graphical abstract

Teaser

Pusapati et al. identify an mTORC1-dependent mechanism of metabolic rewiring that can allow cancer cells to escape glycolysis dependency and show that, importantly, these glycolysis-independent cells are sensitive to combined treatment with a glycolysis inhibitor and an mTORC1 inhibitor.


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