The serine/threonine kinase LKB1 is a tumor suppressor gene mutated in the familial cancer condition Peutz-Jeghers syndrome (PJS), as well as in 30% of sporadic non-small cell lung cancer (NSCLC). One of the critical substrates of LKB1 is the AMP-activated protein kinase (AMPK). AMPK is a highly conserved sensor of cellular energy status found in all eukaryotic cells that restores metabolic homeostasis following stress. Thus LKB1 is a unique energy-state sensitive regulator of growth and metabolic reprogramming via its effects on AMPK. Our laboratory has performed a three-pronged screen to identify novel substrates of AMPK that may mediate its effects on metabolism and growth control. These studies have led to the identification of components of the mTOR signaling pathway (raptor, TSC2), the autophagy pathway (ULK1), and transcriptional regulators of metabolism (Srebp1, HDAC4/5/7) all as direct substrates of AMPK. Collectively, these studies uncovered novel conserved effectors of LKB1 and AMPK that mediate their role as a metabolic checkpoint coordinating cell growth with energy status. The connection of AMPK to tumor suppression has also led many to examine whether compounds that normally serve to activate AMPK, may in fact exhibit anti-cancer activities. Notably, the most widely used type 2 diabetes therapeutic in the US and worldwide, metformin, is a mitochondrial OXPHOS inhibitor which activates AMPK. We have therefore examined the potential anti-cancer effects of metformin and its more potent analog phenformin, in the context of genetically engineered mouse models of lung cancer. Whereas cells containing an intact LKB1-AMPK pathway respond to this metabolic stress by undergoing growth arrest, cells lacking LKB1 are unable to sense the damage and continue to divide ultimately undergoing apoptosis. Thus we examined whether this class of compounds may show selective therapeutic efficacy in preclinical trials in Kras-dependent lung cancer mouse models with loss of LKB1 as compared to those bearing loss of p53.
Citation Format: Reuben J. Shaw. The LKB1-AMPK pathway coordinates metabolic reprogramming with growth control. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PL03-03.