title: LKB1 promotes metabolic flexibility in response to energy stress.
abstract: The Liver Kinase B1 (LKB1) tumor suppressor acts as a metabolic energy sensor to regulate AMP-activated protein kinase (AMPK) signaling and is commonly mutated in various cancers, including non-small cell lung cancer (NSCLC). Tumor cells deficient in LKB1 may be uniquely sensitized to metabolic stresses, which may offer a therapeutic window in oncology. To address this question we have explored how functional LKB1 impacts the metabolism of NSCLC cells using13C metabolic flux analysis. Isogenic NSCLC cells expressing functional LKB1 exhibited higher flux through oxidative mitochondrial pathways compared to those deficient in LKB1. Re-expression of LKB1 also increased the capacity of cells to oxidize major mitochondrial substrates, including pyruvate, fatty acids, and glutamine. Furthermore, LKB1 expression promoted an adaptive response to energy stress induced by anchorage-independent growth. Finally, this diminished adaptability sensitized LKB1-deficient cells to combinatorial inhibition of mitochondrial complex I and glutaminase. Together, our data implicate LKB1 as a major regulator of adaptive metabolic reprogramming and suggest synergistic pharmacological strategies for mitigating LKB1-deficient NSCLC tumor growth.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Parker
authors.affiliation: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Robert U
authors.initials: RU
authors.lastname: Svensson
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Divakaruni
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Austin E
authors.initials: AE
authors.lastname: Lefebvre
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.affiliation: Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Shaw
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. Electronic address: cmetallo@ucsd.edu.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
mesh_terms: D000072283:A549 Cells; D000091162:AMP-Activated Protein Kinase Kinases; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004734:Energy Metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases
keywords: Cancer metabolism; Glutaminase; LKB1; Metabolic flux analysis; Mitochondria; Phenformin