PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway

Ying Huang, Jia Kai Hou, Ting Ting Chen, Xu Yun Zhao, Zhao Wen Yan, Jing Zhang, Jie Yang, Scott C. Kogan, Guo Qiang Chen

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1132-1144
Number of pages13
JournalAutophagy
Volume7
Issue number10
DOIs
StatePublished - Jan 1 2011

Fingerprint

Autophagy
Acute Promyelocytic Leukemia
Proteins
Oncogene Proteins
Transmission Electron Microscopy
Acute Myeloid Leukemia
Bone Marrow Cells
Organelles
Neoplasms
Up-Regulation
Spleen
Therapeutics

Keywords

  • Acute promyelocytic leukemia (APL)
  • Apoptosis
  • Autophagy
  • mTOR
  • PML-RARα

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Huang, Y., Hou, J. K., Chen, T. T., Zhao, X. Y., Yan, Z. W., Zhang, J., ... Chen, G. Q. (2011). PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway. Autophagy, 7(10), 1132-1144. https://doi.org/10.4161/auto.7.10.16636

PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway. / Huang, Ying; Hou, Jia Kai; Chen, Ting Ting; Zhao, Xu Yun; Yan, Zhao Wen; Zhang, Jing; Yang, Jie; Kogan, Scott C.; Chen, Guo Qiang.

In: Autophagy, Vol. 7, No. 10, 01.01.2011, p. 1132-1144.

Research output: Contribution to journalArticle

Huang, Y, Hou, JK, Chen, TT, Zhao, XY, Yan, ZW, Zhang, J, Yang, J, Kogan, SC & Chen, GQ 2011, 'PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway', Autophagy, vol. 7, no. 10, pp. 1132-1144. https://doi.org/10.4161/auto.7.10.16636
Huang, Ying ; Hou, Jia Kai ; Chen, Ting Ting ; Zhao, Xu Yun ; Yan, Zhao Wen ; Zhang, Jing ; Yang, Jie ; Kogan, Scott C. ; Chen, Guo Qiang. / PML-RARα enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway. In: Autophagy. 2011 ; Vol. 7, No. 10. pp. 1132-1144.
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