title: PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway.
abstract: Autophagy is a highly conserved, closely regulated homeostatic cellular activity that allows for the bulk degradation of long-lived proteins and cytoplasmic organelles. Its roles in cancer initiation and progression and in determining the response of tumor cells to anticancer therapy are complicated, and only limited investigation has been conducted on the potential significance of autophagy in the pathogenesis and therapeutic response of acute myeloid leukemia. Here we demonstrate that the inducible or transfected expression of the acute promyelocytic leukemia (APL)-specific PML-RARα, but not PLZF-RARα or NPM-RARα, fusion protein upregulates constitutive autophagy activation in leukemic and nonleukemic cells, as evaluated by hallmarks for autophagy including transmission electron microscopy. The significant increase in autophagic activity is also found in the leukemic cells-infiltrated bone marrow and spleen from PML-RARα-transplanted leukemic mice. The autophagy inhibitor 3-methyladenine significantly abrogates the autophagic events upregulated by PML-RARα, while the autophagic flux assay reveals that the fusion protein induces autophagy by increasing the on-rate of autophagic sequestration. Furthermore, this modulation of autophagy by PML-RARα is possibly mediated by a decreased activation of the Akt/mTOR pathway. Finally, we also show that autophagy contributes to the anti-apoptotic function of the PML-RARα protein. Given the critical role of the PML-RARα oncoprotein in APL pathogenesis, this study suggests an important role of autophagy in the development and treatment of this disease.
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Jia-Kai
authors.initials: JK
authors.lastname: Hou
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Chen
authors.forename: Xu-Yun
authors.initials: XY
authors.lastname: Zhao
authors.forename: Zhao-Wen
authors.initials: ZW
authors.lastname: Yan
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D020298:U937 Cells
chemical_list: C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C025946:3-methyladenine; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000225:Adenine