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, KRAS-driven 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.
Highlights
The tumor suppressor protein phosphatase 2A (PP2A) is a serine/threonine phosphatase whose activity is inhibited in most human cancers
Mice were treated with 15 mg/kg SMAP1 twice a day per previously published, and unpublished data using a range of SMAPs from 0.1 to 50 mg/kg dosed either twice a day or once a day demonstrated that doses between 5 and 15 mg/kg twice a day resulted in optimal tumor growth inhibition (46 – 50)
Phosphorylated MYC and total MYC protein expression were determined to be significantly decreased in SMAP-treated tumors compared with control tumors (Fig. 1, C and D)
Summary
The tumor suppressor protein phosphatase 2A (PP2A) is a serine/threonine phosphatase whose activity is inhibited in most human cancers. We show that direct activation of PP2A by SMAPs in vivo results in tumor growth inhibition across numerous models of MYC-driven cancers and extends previous findings beyond just subcutaneous xenotransplanted models of cancer This current work demonstrates that SMAPs inhibit MYC signaling regardless of the mechanism by which MYC drives any given cancer. We demonstrate that the decrease in MYC protein levels results from changes in MYC protein stability as a result of proteasomemediated protein degradation upon PP2A-mediated dephosphorylation In support of this finding, tumors expressing mutations in the phosphodegron of MYC were no longer responsive to SMAP treatment. Our data show that direct activation of PP2A is a promising therapeutic strategy for the treatment of MYC-driven cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
