AMP-activated protein kinase is essential for survival in chronic hypoxia.
This study was undertaken to interrogate cancer cell survival during long-term hypoxic stress. Two systems with relevance to carcinogenesis were employed: Fully transformed BJ cells and a renal carcinoma cell line (786-0). The dynamic of AMPK activity was consistent with a prosurvival role during chronic hypoxia. This was further supported by the effects of AMPK agonists and antagonists (AICAR and compound C). Expression of a dominant-negative AMPK alpha resulted in a decreased ATP level and significantly compromised survival in hypoxia. Dose-dependent prosurvival effects of rapamycin were consistent with mTOR inhibition being a critical downstream mediator of AMPK in persistent low oxygen.
Borger
Darrell R
DR
Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Mayer Building 440, 44 Binney Street, Boston, MA 02115, USA.
Gavrilescu
L Cristina
LC
Bucur
Maria C
MC
Ivan
Mircea
M
Decaprio
James A
JA
D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D047428:Protein Kinase Inhibitors; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide; D020123:Sirolimus