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- Title
Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms.
- Authors
Chan, Gary K. L.; Maisel, Samantha; Hwang, Yeonjoo C.; Pascual, Bryan C.; Wolber, Rebecca R. B.; Phuong Vu; Patra, Krushna C.; Bouhaddou, Mehdi; Kenerson, Heidi L.; Lim, Huat C.; Donald Long; Yeung, Raymond S.; Sethupathy, Praveen; Swaney, Danielle L.; Krogan, Nevan J.; Turnham, Rigney E.; Riehle, Kimberly J.; Scott, John D.; Bardeesy, Nabeel; Gordan, John D.
- 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.
- Subjects
AURORA kinases; PROTEIN expression; MYC proteins; PROTEIN kinases; CELL growth
- Publication
eLife, 2023, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.69521