Metabolic control points in cancer (85.3)

Abstract

All cells must manage their energetic resources to survive. This is particularly true for cancer cells, which initiate changes in their cellular metabolism as they transition from a normal to a cancerous state. Tumor cells must engage pathways of cellular metabolism to generate the energy and biosynthetic intermediates required to support increased cell growth and division. In addition, for growing tumours, overcoming metabolic stress induced by nutrient limitation and/or hypoxia is a critical step for solid tumour growth. It is now appreciated that many of the predominant mutations observed in cancer also influence tumor metabolism as part of their mode of action. Here I discuss the role that cellular energy sensors ‐ notably the Liver Kinase‐B1 (LKB1) and the AMP‐activated protein kinase (AMPK) ‐ play in regulating tumor metabolism and adaptation to metabolic stress. We have found that the LKB1‐AMPK pathway negatively regulates aerobic glycolysis (the “Warburg effect”) in cancer cells, and that disruption of this pathway promotes a metabolic shift to aerobic glycolysis and supports increased cell growth. This metabolic shift is mediated by the hypoxia‐inducible factor‐1α (HIF‐1α), and silencing HIF‐1α reverses the biosynthetic and proliferative advantages conferred by reduced LKB1‐AMPK signaling. Finally, I will present evidence that AMPK activity is dynamically regulated in tumors to enhance pro‐growth metabolism, but that this pathway is required to maintain tumor cell viability in response to stress. Finally, I will discuss whether metabolic checkpoints serve “suppressive” or “supportive” roles in cancer development and/or progression.This work was supported by grants from the CIHR (MOP‐93799) and CCSRI (700586).