Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors

The spindle checkpoint is essential to ensure proper chromosome segregation and thereby maintain genomic stability. Mitotic arrest deficiency 2 (Mad2), a critical component of the spindle checkpoint, is overexpressed in many cancer cells. Thus, we hypothesized that Mad2 overexpression could specific...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2014-01, Vol.111 (4), p.1628-1633
Main Authors: Bina, Yang, Kitagawa, Risa, Bansal, Parmil K., Yo Fujii, Stepanov, Alexander, Kitagawa, Katsumi
Format: Article
Language:English
Subjects:
Antibodies
Base Sequence
Biological Sciences
Cancer
Cantharidin - pharmacology
Cell cycle
Cell lines
Cells
Chromosomes
Delta cells
DNA Primers
Enzyme Inhibitors - pharmacology
Epithelial cells
Gene expression
Gene Knockdown Techniques
HeLa Cells
Humans
Mad2 Proteins - genetics
Mad2 Proteins - metabolism
Neoplasms - enzymology
Neoplasms - metabolism
Neoplasms - pathology
Phosphorylation
Protein Phosphatase 2 - antagonists & inhibitors
Protein Phosphatase 2 - genetics
RNA, Small Interfering
Small interfering RNA
Tumors
Yeast
Yeasts
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Summary:The spindle checkpoint is essential to ensure proper chromosome segregation and thereby maintain genomic stability. Mitotic arrest deficiency 2 (Mad2), a critical component of the spindle checkpoint, is overexpressed in many cancer cells. Thus, we hypothesized that Mad2 overexpression could specifically make cancer cells susceptible to death by inducing a synthetic dosage lethality defect. Because the spindle checkpoint pathway is highly conserved between yeast and humans, we performed a synthetic genetic array analysis in yeast, which revealed that Mad2 overexpression induced lethality in 13 gene deletions. Among the human homologs of candidate genes, knockdown of PPP2R1A , a gene encoding a constant regulatory subunit of protein phosphatase 2, significantly inhibited the growth of Mad2-overexpressing tumor cells. PPP2R1A inhibition induced Mad2 phosphorylation and suppressed Mad2 protein levels. Depletion of PPP2R1A inhibited colony formation of Mad2-overexpressing HeLa cells but not of unphosphorylated Mad2 mutant-overexpressing cells, suggesting that the lethality induced by PP2A depletion in Mad2-overexpressing cells is dependent on Mad2 phosphorylation. Also, the PP2A inhibitor cantharidin induced Mad2 phosphorylation and inhibited the growth of Mad2-overexpressing cancer cells. Aurora B knockdown inhibited Mad2 phosphorylation in mitosis, resulting in the blocking of PPP2R1A inhibition–induced cell death. Taken together, our results strongly suggest that PP2A is a good therapeutic target in Mad2-overexpressing tumors.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1315588111