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MDM2 Inhibitor, Nutlin 3a, Induces p53 Dependent Autophagy in Acute Leukemia by AMP Kinase Activation

Gautam Borthakur1, Seshagiri Duvvuri1, Vivian Ruvolo1

  • 1Section of Molecular Hematology and Therapy; Departments of Leukemia and Stem Cell Transplantation, UT MD Anderson Cancer Center, Houston, Texas, United States of America.

Plos One
|October 7, 2015
PubMed

Insights

MDM2 inhibitors like Nutlin 3a activate p53 to induce apoptosis in leukemia. This process involves autophagy, which appears to promote cell death, offering a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Pathways

Background:

  • MDM2 inhibitors activate p53, inducing apoptosis in leukemias.
  • p53 modulates programmed cell death pathways, including autophagy.
  • Autophagy's role in p53-mediated apoptosis in leukemia requires further investigation.

Purpose of the Study:

  • To investigate the induction of autophagy in acute leukemia by Nutlin 3a, a first-in-class MDM2 inhibitor.
  • To determine the role of p53 and AMP kinase (AMPK) in Nutlin 3a-induced autophagy.
  • To elucidate whether autophagy acts as a pro-apoptotic or anti-apoptotic mechanism in this context.

Main Methods:

  • Treatment of acute leukemia cells with Nutlin 3a.
  • Assessment of autophagy induction using pharmacological and genetic inhibition.
  • Evaluation of p53 and AMPK dependency using knockout cells and knockdown techniques.

Main Results:

  • Nutlin 3a induced autophagy in a p53-dependent manner.
  • Transcriptional activation of AMPK was critical for Nutlin 3a-induced autophagy.
  • Inhibition of autophagy (pharmacological or genetic) impaired Nutlin 3a-induced apoptosis.

Conclusions:

  • Nutlin 3a induces p53-dependent autophagy in acute leukemia.
  • AMPK activation is essential for this autophagy induction.
  • Autophagy acts as a pro-apoptotic pathway in Nutlin 3a-treated leukemia cells, suggesting a novel therapeutic avenue.

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