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J Clin Invest DOI:10.1172/JCI65093

Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia.

Publication TypeJournal Article
Year of Publication2014
AuthorsGutierrez, A, Pan, L, Groen, RWJ, Baleydier, F, Kentsis, A, Marineau, J, Grebliunaite, R, Kozakewich, E, Reed, C, Pflumio, F, Poglio, S, Uzan, B, Clemons, P, VerPlank, L, An, F, Burbank, J, Norton, S, Tolliday, N, Steen, H, Weng, AP, Yuan, H, Bradner, JE, Mitsiades, C, A Look, T, Aster, JC
JournalJ Clin Invest
Volume124
Issue2
Pages644-55
Date Published2014 Feb
ISSN1558-8238
KeywordsAnimals, Animals, Genetically Modified, Apoptosis, Cell Line, Tumor, Cell Survival, Chromatography, Affinity, Disease Models, Animal, Dopamine Antagonists, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Mass Spectrometry, Mice, Perphenazine, Phenothiazines, Phosphorylation, Pigmentation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein Phosphatase 2, Proteomics, Receptors, Notch, Time Factors, Zebrafish
Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug's antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.

URLhttp://dx.doi.org/10.1172/JCI65093
DOI10.1172/JCI65093
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24401270?dopt=Abstract

Alternate JournalJ. Clin. Invest.
PubMed ID24401270
PubMed Central IDPMC3904599
Grant ListK08 CA160660 / CA / NCI NIH HHS / United States
1K08CA133103 / CA / NCI NIH HHS / United States
P01 CA109901 / CA / NCI NIH HHS / United States
R01 CA176746 / CA / NCI NIH HHS / United States
5P01CA109901 / CA / NCI NIH HHS / United States
K08 CA133103 / CA / NCI NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States