Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms
- University of California, San Francisco, United States
- Harvard Medical School, United States
- University of Washington, United States
- 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.
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TCGA pan-cancer atlasTCGA pan-cancer atlas / NA.
Article and author information
Author details
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.
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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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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