Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK.
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.
Departments of Oncology, Experimental Hematology and Cancer Biology, and Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45242.
Xiaona
X
Liu
Rishi Raj
RR
Chhipa
Shabnam
S
Pooya
Matthew
M
Wortman
Sara
S
Yachyshin
Lionel M L
LM
Chow
Ashish
A
Kumar
Xuan
X
Zhou
Ying
Y
Sun
Brian
B
Quinn
Christopher
C
McPherson
Ronald E
RE
Warnick
Ady
A
Kendler
Shailendra
S
Giri
Jeroen
J
Poels
Koenraad
K
Norga
Benoit
B
Viollet
Gregory A
GA
Grabowski
Biplab
B
Dasgupta
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011494:Protein Kinases / Q000187:drug effects* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
D008687:Metformin; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases
glioma; metabolism