Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α

Brandon Faubert, Emma E Vincent, Takla Griss, Bozena Samborska, Said Izreig, Robert U Svensson, Orval A Mamer, Daina Avizonis, David B Shackelford, Reuben J Shaw, Russell G Jones

Research output: Contribution to journalArticle (Academic Journal)peer-review

117 Citations (Scopus)

Abstract

One of the major metabolic changes associated with cellular transformation is enhanced nutrient utilization, which supports tumor progression by fueling both energy production and providing biosynthetic intermediates for growth. The liver kinase B1 (LKB1) is a serine/threonine kinase and tumor suppressor that couples bioenergetics to cell-growth control through regulation of mammalian target of rapamycin (mTOR) activity; however, the influence of LKB1 on tumor metabolism is not well defined. Here, we show that loss of LKB1 induces a progrowth metabolic program in proliferating cells. Cells lacking LKB1 display increased glucose and glutamine uptake and utilization, which support both cellular ATP levels and increased macromolecular biosynthesis. This LKB1-dependent reprogramming of cell metabolism is dependent on the hypoxia-inducible factor-1α (HIF-1α), which accumulates under normoxia in LKB1-deficient cells and is antagonized by inhibition of mTOR complex I signaling. Silencing HIF-1α reverses the metabolic advantages conferred by reduced LKB1 signaling and impairs the growth and survival of LKB1-deficient tumor cells under low-nutrient conditions. Together, our data implicate the tumor suppressor LKB1 as a central regulator of tumor metabolism and growth control through the regulation of HIF-1α-dependent metabolic reprogramming.

Original languageEnglish
Pages (from-to)2554-2559
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number7
DOIs
Publication statusPublished - 18 Feb 2014

Keywords

  • Adenosine Triphosphate
  • Analysis of Variance
  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation
  • Energy Metabolism
  • Fibroblasts
  • Gas Chromatography-Mass Spectrometry
  • Glucose
  • Glutamine
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Metabolic Networks and Pathways
  • Mice
  • Multiprotein Complexes
  • Oxygen Consumption
  • Protein-Serine-Threonine Kinases
  • Reactive Oxygen Species
  • TOR Serine-Threonine Kinases
  • Journal Article
  • Research Support, Non-U.S. Gov't

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