PMID- 24550282
OWN - NLM
STAT- MEDLINE
DCOM- 20140415
LR  - 20220317
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 111
IP  - 7
DP  - 2014 Feb 18
TI  - Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer 
      cells via HIF-1alpha.
PG  - 2554-9
LID - 10.1073/pnas.1312570111 [doi]
AB  - 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-1alpha (HIF-1alpha), which 
      accumulates under normoxia in LKB1-deficient cells and is antagonized by 
      inhibition of mTOR complex I signaling. Silencing HIF-1alpha 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-1alpha-dependent 
      metabolic reprogramming.
FAU - Faubert, Brandon
AU  - Faubert B
AD  - Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
FAU - Vincent, Emma E
AU  - Vincent EE
FAU - Griss, Takla
AU  - Griss T
FAU - Samborska, Bozena
AU  - Samborska B
FAU - Izreig, Said
AU  - Izreig S
FAU - Svensson, Robert U
AU  - Svensson RU
FAU - Mamer, Orval A
AU  - Mamer OA
FAU - Avizonis, Daina
AU  - Avizonis D
FAU - Shackelford, David B
AU  - Shackelford DB
FAU - Shaw, Reuben J
AU  - Shaw RJ
FAU - Jones, Russell G
AU  - Jones RG
LA  - eng
GR  - P01 CA120964/CA/NCI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - MOP-93799/CAPMC/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140203
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Reactive Oxygen Species)
RN  - 0RH81L854J (Glutamine)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (STK11 protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Adenosine Triphosphate/metabolism
MH  - Analysis of Variance
MH  - Animals
MH  - Apoptosis/physiology
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Energy Metabolism/*physiology
MH  - Fibroblasts
MH  - Gas Chromatography-Mass Spectrometry
MH  - Glucose/metabolism
MH  - Glutamine/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Metabolic Networks and Pathways/*genetics/physiology
MH  - Mice
MH  - Multiprotein Complexes/metabolism
MH  - Oxygen Consumption/physiology
MH  - Protein Serine-Threonine Kinases/*deficiency/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC3932920
OTO - NOTNLM
OT  - HIF-1alpha
OT  - PJS
OT  - Peutz-Jeghers Syndrome
OT  - Warburg effect
OT  - cancer metabolism
OT  - glutamine metabolism
COIS- The authors declare no conflict of interest.
EDAT- 2014/02/20 06:00
MHDA- 2014/04/16 06:00
PMCR- 2014/08/18
CRDT- 2014/02/20 06:00
PHST- 2014/02/20 06:00 [entrez]
PHST- 2014/02/20 06:00 [pubmed]
PHST- 2014/04/16 06:00 [medline]
PHST- 2014/08/18 00:00 [pmc-release]
AID - 1312570111 [pii]
AID - 201312570 [pii]
AID - 10.1073/pnas.1312570111 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2554-9. doi: 
      10.1073/pnas.1312570111. Epub 2014 Feb 3.