AMP-activated protein kinase is involved in neural stem cell growth suppression and cell cycle arrest by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside and glucose deprivation by down-regulating phospho-retinoblastoma protein and cyclin D.
The fate of neural stem cells (NSCs), including their proliferation, differentiation, survival, and death, is regulated by multiple intrinsic signals and the extrinsic environment. We had previously reported that 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) directly induces astroglial differentiation of NSCs by activation of the Janus kinase (JAK)/Signal transducer and activator of transcription 3 (STAT3) pathway independently of AMP-activated protein kinase (AMPK). Here, we reported the observation that AICAR inhibited NSC proliferation and its underlying mechanism. Analysis of caspase activity and cell cycle showed that AICAR induced G1/G0 cell cycle arrest in NSCs, associated with decreased levels of poly(ADP-ribose) polymerase, phospho-retinoblastoma protein (Rb), and cyclin D but did not cause apoptosis. Iodotubericidin and Compound C, inhibitors of adenosine kinase and AMPK, respectively, or overexpression of a dominant-negative mutant of AMPK, but not JAK inhibitor, were able to reverse the anti-proliferative effect of AICAR. Glucose deprivation also activated the AMPK pathway, induced G0/G1 arrest, and suppressed the proliferation of NSCs, an effect associated with decreased levels of phospho-Rb and cyclin D protein. Furthermore, Compound C and overexpression of dominant-negative AMPK in C17.2 NSCs could block the glucose deprivation-mediated down-regulation of cyclin D and partially reverse the suppression of proliferation. These results suggest that AICAR and glucose deprivation might induce G1/G0 cell cycle arrest and suppress proliferation of NSCs via phospho-Rb and cyclin D down-regulation. AMPK, but not JAK/STAT3, activation is key for this inhibitory effect and may play an important role in the responses of NSCs to metabolic stresses such as glucose deprivation.
Zang
Yi
Y
National Center for Drug Screening and Neurological Pharmacology Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Yu
Li-Fang
LF
Nan
Fa-Jun
FJ
Feng
Lin-Yin
LY
Li
Jia
J
D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D013549:Sweetening Agents / Q000494:pharmacology*
D056741:Cyclin D; D016213:Cyclins; D007004:Hypoglycemic Agents; D011720:Pyrazoles; D011743:Pyrimidines; D016160:Retinoblastoma Protein; D012265:Ribonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D013549:Sweetening Agents; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; D053612:Janus Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide; D005947:Glucose