Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth
Jaya Sangodkar, … , Michael Ohlmeyer, Goutham Narla
Jaya Sangodkar, … , Michael Ohlmeyer, Goutham Narla
Published May 15, 2017
Citation Information: J Clin Invest. 2017;127(6):2081-2090. https://doi.org/10.1172/JCI89548.
View: Text | PDF
Concise Communication Genetics Oncology

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

Abstract

Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers. Our group previously developed a series of orally bioavailable small molecule activators of PP2A, termed SMAPs. We now report that SMAP treatment inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models. Mechanistically, we found that SMAPs act by binding to the PP2A Aα scaffold subunit to drive conformational changes in PP2A. These results show that PP2A can be activated in cancer cells to inhibit proliferation. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases and represents an advancement toward the development of small molecule activators of tumor suppressor proteins.

Authors

Jaya Sangodkar, Abbey Perl, Rita Tohme, Janna Kiselar, David B. Kastrinsky, Nilesh Zaware, Sudeh Izadmehr, Sahar Mazhar, Danica D. Wiredja, Caitlin M. O’Connor, Divya Hoon, Neil S. Dhawan, Daniela Schlatzer, Shen Yao, Daniel Leonard, Alain C. Borczuk, Giridharan Gokulrangan, Lifu Wang, Elena Svenson, Caroline C. Farrington, Eric Yuan, Rita A. Avelar, Agnes Stachnik, Blake Smith, Vickram Gidwani, Heather M. Giannini, Daniel McQuaid, Kimberly McClinch, Zhizhi Wang, Alice C. Levine, Rosalie C. Sears, Edward Y. Chen, Qiaonan Duan, Manish Datt, Shozeb Haider, Avi Ma’ayan, Analisa DiFeo, Neelesh Sharma, Matthew D. Galsky, David L. Brautigan, Yiannis A. Ioannou, Wenqing Xu, Mark R. Chance, Michael Ohlmeyer, Goutham Narla

×

Figure 4

SMAPs binding to protein phosphatase PP2A.

Options: View larger image (or click on image) Download as PowerPoint
SMAPs binding to protein phosphatase PP2A. (A) Binding studies of radiol...
(A) Binding studies of radiolabeled SMAPs with PP2A AC dimer, lysozyme, and PP1 using equilibrium dialysis. (B) Binding of radiolabeled SMAPs to lysozyme as negative control and PP2A (A–C) subunits using equilibrium dialysis. (C) Quantification of the KD and binding maximum (Bmax) for SMAP against the PP2A trimer. Data represent mean ± SD of 3 experiments. (D) Projection of changes in solvent exposure based on hydroxylradical modification in the A subunit of PP2A AC upon SMAP ligand addition. The structure of the A subunit (in light gray) is taken from 2A (PP2A) holoenzyme (PDB 2IAE). Modified amino acids are represented by colored side chains. The color codes indicate the changes in rates of modification for each specific site upon SMAP binding to the A subunit of PP2A AC. Purple indicates the residues that showed change in modification of less than 0.5-fold, blue indicates the residues that show minimal to no change (< 2-fold) in modification, green indicates decreases of more than 2-fold and less than 4-fold, yellow indicates decreases of more than 4-fold and less than 6-fold, orange indicates decreases of more than 6-fold and less than 9-fold, and red indicates decreases of more than 9-fold in the modification rate upon SMAP binding. Data represent mean ± SEM. *P < 0.05, Student’s t test.