Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms
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 carcinoma (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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 24, 2023
- Source ID
- 10.7554/elife.69521
Entities
People
- Bryan C Pascual
- Danielle L Swaney
- Donald Long
- Gary K. L. Chan
- Heidi L. Kenerson
- Huat C Lim
- John D Gordan
- John D. Scott
- Kimberly J Riehle
- Krushna C Patra
- Mehdi Bouhaddou
- Nabeel Bardeesy
- Nevan J. Krogan
- Phuong Vu
- Praveen Sethupathy
- Raymond S Yeung
- Rebecca Rb Wolber
- Rigney E Turnham
- Samantha Maisel
- Yeonjoo C. Hwang
Organizations
- Burroughs Wellcome Fund
- Cornell University
- Fibrolamellar Cancer Foundation
- Gladstone Institutes
- Harvard University
- Hope Funds for Cancer Research
- Massachusetts General Hospital
- National Center for Advancing Translational Sciences
- National Institutes of Health
- University of California, San Francisco
- University of Washington
- University of Washington Medical Center