title: 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.
abstract: 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.
authors.affiliation: National Center for Drug Screening and Neurological Pharmacology Department, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zang
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yu
authors.forename: Fa-Jun
authors.initials: FJ
authors.lastname: Nan
authors.forename: Lin-Yin
authors.initials: LY
authors.lastname: Feng
authors.forename: Jia
authors.initials: J
authors.lastname: Li
mesh_terms: 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*
chemical_list: 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