LKB1 promotes metabolic flexibility in response to energy stress

• Published in: Metabolic engineering Vol. 43; no. Pt B; pp. 208 - 217
• Main Authors: Parker, Seth J., Svensson, Robert U., Divakaruni, Ajit S., Lefebvre, Austin E., Murphy, Anne N., Shaw, Reuben J., Metallo, Christian M.
• Format: Journal Article
• Language: English
• Published: Belgium Elsevier Inc 01.09.2017
• Subjects: Cancer metabolism; Glutaminase; LKB1; Metabolic flux analysis; Mitochondria; Phenformin; Mitochondria; Cancer metabolism; LKB1; Metabolic flux analysis; Phenformin; Glutaminase
• ISSN: 1096-7176; 1096-7184
• DOI: 10.1016/j.ymben.2016.12.010

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 using 13C 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. •LKB1 deficiency reprograms mitochondrial metabolism in NSCLC.•LKB1 promotes metabolic flexibility in the context of energetic stress.•LKB1 deficiency sensitizes cells to phenformin and glutaminase inhibitor treatment.