Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers

Caroline C. Farrington, Eric Yuan, Sahar Mazhar, Sudeh Izadmehr, Lauren Hurst, Brittany L. Allen-Petersen, Mahnaz Janghorban, Eric Chung, Grace Wolczanski, Matthew Galsky, Rosalie Sears, Jaya Sangodkar, Goutham Narla

Research output: Contribution to journalArticle

Abstract

The tumor suppressor protein phosphatase 2A (PP2A) is a serine/threonine phosphatase whose activity is inhibited in most human cancers. One of the best-characterized PP2A substrates is MYC proto-oncogene basic helix-loop-helix transcription factor (MYC), whose overexpression is commonly associated with aggressive forms of this disease. PP2A directly dephosphorylates MYC, resulting in its degradation. To explore the therapeutic potential of direct PP2A activation in a diverse set of MYC-driven cancers, here we used biochemical assays, recombinant cell lines, gene expression analyses, and immunohistochemistry to evaluate a series of first-in-class small-molecule activators of PP2A (SMAPs) in Burkitt lymphoma, KRASdriven non-small cell lung cancer, and triple-negative breast cancer. In all tested models of MYC-driven cancer, the SMAP treatment rapidly and persistently inhibited MYC expression through proteasome-mediated degradation, inhibition of MYC transcriptional activity, decreased cancer cell proliferation, and tumor growth inhibition. Importantly, we generated a series of cell lines expressing PP2A-dependent phosphodegron variants of MYC and demonstrated that the antitumorigenic activity of SMAPs depends on MYC degradation. Collectively, the findings presented here indicate a pharmacologically tractable approach to drive MYC degradation by using SMAPs for the management of a broad range of MYC-driven cancers.

Original languageEnglish (US)
Pages (from-to)757-770
Number of pages14
JournalJournal of Biological Chemistry
Volume295
Issue number3
DOIs
StatePublished - Jan 17 2020

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Farrington, C. C., Yuan, E., Mazhar, S., Izadmehr, S., Hurst, L., Allen-Petersen, B. L., Janghorban, M., Chung, E., Wolczanski, G., Galsky, M., Sears, R., Sangodkar, J., & Narla, G. (2020). Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers. Journal of Biological Chemistry, 295(3), 757-770. https://doi.org/10.1074/jbc.RA119.011443