ROS-driven Akt dephosphorylation at Ser-473 is involved in 4-HPR-mediated apoptosis in NB4 cells.
N-(4-hydroxyphenyl) retinamide (4-HPR), as a synthetic retinoid, has been shown to inhibit carcinogenesis in a variety of cancers. Extensive studies have indicated that ROS are involved in 4-HPR-mediated apoptosis. Herein, we provide further evidence that the Akt signaling pathway is involved in 4-HPR-mediated apoptosis. Of note is the fact that the expression of PI3K (p110) does not change obviously, and neither LY294002 nor insulin could influence the apoptosis induced by 4-HPR. These observations implicate the direct interaction between Akt and ROS. Our data also reveal that 4-HPR-mediated ROS evoke Akt conformational change by forming an intramolecular disulfide bond; N-acetylcysteine and glutathione, as thiol antioxidants, significantly abate the ROS generation in 4-HPR-exposed cells. Further experiments indicate that the conformational change in Akt not only disrupts Akt-Hsp90 binding, but also enhances Akt-PP2A interaction. All these results collectively suggest that 4-HPR-induced apoptosis is associated with a ROS-mediated conformational change in Akt, and this change, as a consequence, mediates dephosphorylation of Akt via regulating Akt-Hsp90 or Akt-PP2A complex formation.
Cao
Ji
J
Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Xu
Danqing
D
Wang
Duoduo
D
Wu
Rui
R
Zhang
Lei
L
Zhu
Hong
H
He
Qiaojun
Q
Yang
Bo
B
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D009025:Morpholines / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000737:chemistry / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism
D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D017313:Fenretinide; D009025:Morpholines; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D012694:Serine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one