1. Cancer Biology
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MARCH5 mediates NOXA-dependent MCL1 degradation driven by kinase inhibitors and integrated stress response activation

  1. Seiji Arai
  2. Andreas Varkaris
  3. Mannan Nouri
  4. Sen Chen
  5. Lisha Xie
  6. Steven P Balk  Is a corresponding author
  1. Beth Israel Deaconess Medical Center, United States
Research Article
  • Cited 2
  • Views 1,216
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Cite this article as: eLife 2020;9:e54954 doi: 10.7554/eLife.54954

Abstract

MCL1 has critical antiapoptotic functions and its levels are tightly regulated by ubiquitylation and degradation, but mechanisms that drive this degradation, particularly in solid tumors, remain to be established. We show here in prostate cancer cells that increased NOXA, mediated by kinase inhibitor activation of an integrated stress response, drives the degradation of MCL1, and identify the mitochondria-associated ubiquitin ligase MARCH5 as the primary mediator of this NOXA-dependent MCL1 degradation. Therapies that enhance MARCH5-mediated MCL1 degradation markedly enhance apoptosis in response to a BH3 mimetic agent targeting BCLXL, which may provide for a broadly effective therapy in solid tumors. Conversely, increased MCL1 in response to MARCH5 loss does not sensitize to BH3 mimetic drugs targeting MCL1, but instead also sensitizes to BCLXL inhibition, revealing a codependence between MARCH5 and MCL1 that may also be exploited in tumors with MARCH5 genomic loss.

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Author details

  1. Seiji Arai

    Medicine, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9514-735X
  2. Andreas Varkaris

    Medicine, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mannan Nouri

    Medicine, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sen Chen

    Medicine, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lisha Xie

    Medicine, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Steven P Balk

    Medicine, Beth Israel Deaconess Medical Center, Boston, United States
    For correspondence
    sbalk@bidmc.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4546-7371

Funding

National Cancer Institute (P01 CA163227)

  • Steven P Balk

Congressionally Directed Medical Research Programs (W81XWH-16-1-0431)

  • Steven P Balk

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kay F Macleod, University of Chicago, United States

Publication history

  1. Received: January 7, 2020
  2. Accepted: June 1, 2020
  3. Accepted Manuscript published: June 2, 2020 (version 1)
  4. Version of Record published: June 16, 2020 (version 2)

Copyright

© 2020, Arai et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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