LKB1 promotes metabolic flexibility in response to energy stress |
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| Affiliation: | 1. Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA;2. Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA;3. Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA;4. Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA;1. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;1. Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden;2. Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden;3. Departments of Medicine & Pharmacology, University of California, San Diego, USA;1. The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA;2. Dana–Farber Cancer Institute, Boston, MA 02115, USA;3. Children’s Medical Center Research Institute, Department of Pediatrics, and Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390 |
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| 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 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. |
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| Keywords: | LKB1 Cancer metabolism Mitochondria Metabolic flux analysis Phenformin Glutaminase |
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