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Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells
Raju V Pusapati1, Anneleen Daemen2, Catherine Wilson1
1Department of Discovery Oncology, Genentech Inc, South San Francisco, CA 94080, USA.
Abstract:
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.
Insights
Cancer cells can evade glycolysis inhibitors through metabolic reprogramming. Targeting both glycolysis and mTORC1 signaling offers a novel therapeutic strategy against the Warburg effect.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Glycolysis is elevated in many tumors, but targeting it therapeutically has failed, possibly due to cancer cell metabolic plasticity.
- Cancer cells exhibit metabolic flexibility, enabling them to adapt to therapeutic interventions like glycolysis inhibition.
Purpose of the Study:
- To investigate the metabolic reprogramming mechanisms that allow cancer cells to escape a continuous glycolytic block.
- To identify novel therapeutic strategies for overcoming resistance to glycolysis-targeted cancer therapies.
Main Methods:
- Utilized cancer cell models with a continuous glycolytic block.
- Analyzed metabolic flux and signaling pathways, focusing on mTORC1 (mechanistic Target of Rapamycin Complex 1).
- Evaluated the efficacy of combined glycolysis and mTORC1 inhibition in vitro and in vivo.
Main Results:
- Identified sustained mTORC1 signaling as a key mechanism for escaping glycolytic addiction.
- Demonstrated that active mTORC1 redirects glucose through the pentose phosphate pathway to sustain glycolysis.
- Showed that combined inhibition of glycolysis and mTORC1 disrupts metabolic reprogramming and inhibits tumor growth.
Conclusions:
- Sustained mTORC1 signaling is crucial for cancer cell adaptation to glycolysis blockade.
- Combined targeting of glycolysis and mTORC1 represents a promising therapeutic approach for cancer treatment.
- These findings offer new strategies to exploit the Warburg effect for therapeutic benefit.
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