The role of Akt on arsenic trioxide suppression of 3T3-L1 preadipocyte differentiation.
The present study investigates the molecular details of how arsenic trioxide inhibits preadipocyte differentiation and examines the role of Akt/PKB in regulation of differentiation and apoptosis. Continual exposure of arsenic trioxide, at the clinic achievable dosage that does not induce apoptosis, suppressed 3T3-L1 cell differentiation into fat cells by inhibiting the expression of PPARgamma and C/EBPalpha and disrupting the interaction between PPARgamma and RXRalpha, which determines the programming of the adipogenic genes. Interestingly, if we treated the cells for 12 or 24 h and then withdrew arsenic trioxide, the cells were able to differentiate to the comparable levels of untreated cells as assayed by the activity of GAPDH, the biochemical marker of preadipocyte differentiation. Long term treatment blocked the differentiation and the activity of GAPDH could not recover to the comparable levels of untreated cells. Continual exposure of arsenic trioxide caused accumulation in G2/M phase and the accumulation of p21. We found that arsenic trioxide induced the expression and the phosphorylation of Akt/PKB and it inhibited the interaction between Akt/PKB and PPARgamma . Akt/PKB inhibitor appears to block the arsenic trioxide suppression of differentiation. Our results suggested that Akt/PKB may play a role in suppression of apoptosis and negatively regulate preadipocyte differentiation.
Wang
Zhi Xin
ZX
State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Jiang
Chun Sun
CS
Liu
Lei
L
Wang
Xiao Hui
XH
Jin
Hai Jing
HJ
Wu
Qiao
Q
Chen
Quan
Q
D041721:3T3-L1 Cells / Q000187:drug effects / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010087:Oxides / Q000494:pharmacology*; D047495:PPAR gamma / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; D022763:CCAAT-Enhancer-Binding Protein-alpha; D010087:Oxides; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D051057:Proto-Oncogene Proteins c-akt; D000077237:Arsenic Trioxide