Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms

  1. Gary KL Chan
  2. Samantha Maisel
  3. Yeonjoo C Hwang
  4. Bryan C Pascual
  5. Rebecca RB Wolber
  6. Phuong Vu
  7. Krushna C Patra
  8. Mehdi Bouhaddou
  9. Heidi L Kenerson
  10. Huat C Lim
  11. Donald Long
  12. Raymond S Yeung
  13. Praveen Sethupathy
  14. Danielle L Swaney
  15. Nevan J Krogan
  16. Rigney E Turnham
  17. Kimberly J Riehle
  18. John D Scott
  19. Nabeel Bardeesy
  20. John D Gordan  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Harvard Medical School, United States
  3. University of Washington, United States
  4. Cornell University, United States

Abstract

Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer. Two signaling networks were identified downstream of PKA: RAS/MAPK components, and an Aurora Kinase A (AURKA) /glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins. Findings were validated in two PKA-dependent cancer models: a novel, patient-derived fibrolamellar liver cancer (FLC) line that expresses a DNAJ-PKAc fusion, and a PKA-addicted melanoma model with a mutant Type I PKA regulatory subunit. We identify PKA signals that can influence both de novo translation and stability of the proto-oncogene c-MYC. However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Mass spectrometry RAW mass spectrum files have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD025508.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Gary KL Chan

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Samantha Maisel

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yeonjoo C Hwang

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bryan C Pascual

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rebecca RB Wolber

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Phuong Vu

    Department of Medicine, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Krushna C Patra

    Department of Medicine, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Mehdi Bouhaddou

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Heidi L Kenerson

    Department of Surgery, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Huat C Lim

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Donald Long

    Department of Biomedical Sciences, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Raymond S Yeung

    Department of Surgery, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Praveen Sethupathy

    Department of Biomedical Sciences, Cornell University, Ithaca, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Danielle L Swaney

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6119-6084
  15. Nevan J Krogan

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Rigney E Turnham

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Kimberly J Riehle

    Department of Surgery, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. John D Scott

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0367-8146
  19. Nabeel Bardeesy

    Department of Medicine, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. John D Gordan

    Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
    For correspondence
    John.Gordan@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8997-5725

Funding

Fibrolamellar Cancer Foundation (N/A)

  • John D Gordan

Burroughs Wellcome Fund Career Award (N/A)

  • John D Gordan

Fibrolamellar Cancer Foundation (N/A)

  • Nabeel Bardeesy

Fibrolamellar Cancer Foundation (N/A)

  • John D Scott

National Institutes of Health (DK119192)

  • John D Scott

DOD Peer Reviewed Cancer Research Program (12715138)

  • Raymond S Yeung

National Institutes of Health (F32CA239333)

  • Mehdi Bouhaddou

National Institutes of Health (U54 CA209891)

  • Nevan J Krogan

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

Ethics

Human subjects: Human FLCs and paired normal livers were obtained from the University of Washington Medical Center and Seattle Children's Hospital after institutional review board approval (SCH IRB #15277). For prospective fresh tissue collections, informed consent was obtained from the subject and/or parent prior to resection.

Reviewing Editor

  1. Ivan Topisirovic, Jewish General Hospital, Canada

Publication history

  1. Received: April 17, 2021
  2. Accepted: January 22, 2023
  3. Accepted Manuscript published: January 24, 2023 (version 1)

Copyright

© 2023, Chan 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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  1. Gary KL Chan
  2. Samantha Maisel
  3. Yeonjoo C Hwang
  4. Bryan C Pascual
  5. Rebecca RB Wolber
  6. Phuong Vu
  7. Krushna C Patra
  8. Mehdi Bouhaddou
  9. Heidi L Kenerson
  10. Huat C Lim
  11. Donald Long
  12. Raymond S Yeung
  13. Praveen Sethupathy
  14. Danielle L Swaney
  15. Nevan J Krogan
  16. Rigney E Turnham
  17. Kimberly J Riehle
  18. John D Scott
  19. Nabeel Bardeesy
  20. John D Gordan
(2023)
Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms
eLife 12:e69521.
https://doi.org/10.7554/eLife.69521
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