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A chemical biology approach identifies AMPK as a modulator of melanoma oncogene MITF

V Borgdorff1, U Rix2, G E Winter2

  • 11] Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria [2] CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Oncogene
|June 4, 2013
PubMed

Insights

Midostaurin and sunitinib drugs reduce microphthalmia-associated transcription factor (MITF) levels by targeting AMP-activated kinase (AMPK). This AMPK-mediated regulation impacts MITF protein stability and melanocytic cell viability.

Area of Science:

  • Molecular biology
  • Cancer research
  • Cell biology

Background:

  • Microphthalmia-associated transcription factor (MITF) is crucial for melanocytic cell survival and is an oncogene in melanoma.
  • Directly targeting MITF activity with drugs is challenging.
  • Understanding MITF regulation is key for melanoma treatment.

Purpose of the Study:

  • To identify drugs that downregulate MITF expression or activity.
  • To investigate the upstream modulators of MITF targeted by these drugs.
  • To elucidate the mechanism by which MITF levels are regulated in melanocytic cells.

Main Methods:

  • Screening of drug panels for MITF modulation.
  • Chemical proteomic analysis to identify drug targets.
  • RNA interference and chemical inhibition of identified targets.
  • Assessment of MITF protein levels, phosphorylation, and degradation pathways.
  • Evaluation of cell viability upon target inhibition.

Main Results:

  • Multi-kinase inhibitors midostaurin and sunitinib were found to decrease MITF protein levels.
  • AMP-activated kinase (AMPK) was identified as a shared target of these drugs.
  • Inhibition of AMPK led to reduced MITF protein levels via proteasomal degradation.
  • ERK-mediated phosphorylation of MITF preceded its degradation.
  • AMPK inhibition resulted in decreased melanocytic cell viability.

Conclusions:

  • AMP-activated kinase (AMPK) is a key regulator of MITF protein levels in melanocytic cells.
  • Targeting AMPK offers a potential strategy to downregulate MITF in melanoma.
  • The findings provide insights into the post-translational regulation of MITF.

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