ROS-driven Akt dephosphorylation at Ser-473 is involved in 4-HPR-mediated apoptosis in NB4 cells.

Abstract

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.

• Authors: Ji Cao, Danqing Xu, Duoduo Wang, Rui Wu, Lei Zhang, Hong Zhu, Qiaojun He, Bo Yang
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 47 Issue 5 Pg. 536-47 (Sep 01 2009) ISSN: 1873-4596 [Electronic] United States
• PMID: 19482076 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chromones
• Enzyme Inhibitors
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Reactive Oxygen Species
• Fenretinide
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Serine
• Oncogene Protein v-akt

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Chromones (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Female
• Fenretinide (pharmacology)
• HL-60 Cells
• Humans
• K562 Cells
• Leukemia (metabolism, pathology)
• Mice
• Models, Biological
• Models, Molecular
• Morpholines (pharmacology)
• Oncogene Protein v-akt (chemistry, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism, physiology)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Reactive Oxygen Species (pharmacology)
• Serine (metabolism)