PMID- 24474794
OWN - NLM
STAT- MEDLINE
DCOM- 20140506
LR  - 20220311
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 111
IP  - 4
DP  - 2014 Jan 28
TI  - Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists 
      independent of AMPK.
PG  - E435-44
LID - 10.1073/pnas.1311121111 [doi]
AB  - The multifunctional AMPK-activated protein kinase (AMPK) is an evolutionarily 
      conserved energy sensor that plays an important role in cell proliferation, 
      growth, and survival. It remains unclear whether AMPK functions as a tumor 
      suppressor or a contextual oncogene. This is because although on one hand active 
      AMPK inhibits mammalian target of rapamycin (mTOR) and lipogenesis--two crucial 
      arms of cancer growth--AMPK also ensures viability by metabolic reprogramming in 
      cancer cells. AMPK activation by two indirect AMPK agonists AICAR and metformin 
      (now in over 50 clinical trials on cancer) has been correlated with reduced 
      cancer cell proliferation and viability. Surprisingly, we found that compared 
      with normal tissue, AMPK is constitutively activated in both human and mouse 
      gliomas. Therefore, we questioned whether the antiproliferative actions of AICAR 
      and metformin are AMPK independent. Both AMPK agonists inhibited proliferation, 
      but through unique AMPK-independent mechanisms and both reduced tumor growth in 
      vivo independent of AMPK. Importantly, A769662, a direct AMPK activator, had no 
      effect on proliferation, uncoupling high AMPK activity from inhibition of 
      proliferation. Metformin directly inhibited mTOR by enhancing PRAS40's 
      association with RAPTOR, whereas AICAR blocked the cell cycle through proteasomal 
      degradation of the G2M phosphatase cdc25c. Together, our results suggest that 
      although AICAR and metformin are potent AMPK-independent antiproliferative 
      agents, physiological AMPK activation in glioma may be a response mechanism to 
      metabolic stress and anticancer agents.
FAU - Liu, Xiaona
AU  - Liu X
AD  - Departments of Oncology, Experimental Hematology and Cancer Biology, and Human 
      Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45242.
FAU - Chhipa, Rishi Raj
AU  - Chhipa RR
FAU - Pooya, Shabnam
AU  - Pooya S
FAU - Wortman, Matthew
AU  - Wortman M
FAU - Yachyshin, Sara
AU  - Yachyshin S
FAU - Chow, Lionel M L
AU  - Chow LM
FAU - Kumar, Ashish
AU  - Kumar A
FAU - Zhou, Xuan
AU  - Zhou X
FAU - Sun, Ying
AU  - Sun Y
FAU - Quinn, Brian
AU  - Quinn B
FAU - McPherson, Christopher
AU  - McPherson C
FAU - Warnick, Ronald E
AU  - Warnick RE
FAU - Kendler, Ady
AU  - Kendler A
FAU - Giri, Shailendra
AU  - Giri S
FAU - Poels, Jeroen
AU  - Poels J
FAU - Norga, Koenraad
AU  - Norga K
FAU - Viollet, Benoit
AU  - Viollet B
FAU - Grabowski, Gregory A
AU  - Grabowski GA
FAU - Dasgupta, Biplab
AU  - Dasgupta B
LA  - eng
GR  - P30 DK090971/DK/NIDDK NIH HHS/United States
GR  - R01 NS075291/NS/NINDS NIH HHS/United States
GR  - 1R01NS075291-01A1/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140113
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  - 9100L32L2N (Metformin)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Animals
MH  - Brain Neoplasms/enzymology/metabolism/pathology
MH  - Cell Cycle/*physiology
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Glioblastoma/enzymology/metabolism/pathology
MH  - Humans
MH  - Lipogenesis/drug effects
MH  - Metformin/pharmacology
MH  - Mice
MH  - Mice, Knockout
MH  - Protein Kinases/*drug effects/genetics
MH  - TOR Serine-Threonine Kinases/*physiology
PMC - PMC3910576
OTO - NOTNLM
OT  - glioma
OT  - metabolism
COIS- The authors declare no conflict of interest.
EDAT- 2014/01/30 06:00
MHDA- 2014/05/07 06:00
PMCR- 2014/07/28
CRDT- 2014/01/30 06:00
PHST- 2014/01/30 06:00 [entrez]
PHST- 2014/01/30 06:00 [pubmed]
PHST- 2014/05/07 06:00 [medline]
PHST- 2014/07/28 00:00 [pmc-release]
AID - 1311121111 [pii]
AID - 201311121 [pii]
AID - 10.1073/pnas.1311121111 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):E435-44. doi: 
      10.1073/pnas.1311121111. Epub 2014 Jan 13.