Title: Abstract 3662: Analysis of the tumor suppressor function of B55alpha, the PP2A regulatory subunit encoded by PPP2R2A, in prostate cancer cells
Abstract: Abstract Genome wide DNA copy number studies in prostate cancer (PCa) have identified deletions on chromosome 8p21.2 affecting the PPP2R2A gene, which encodes B55α, a B regulatory subunit of Protein Phosphatase 2A (PP2A). The frequency of PPP2R2A hemizygous and homozygous deletions in prostate tumors is 38-58% and 2-7%, respectively. Moreover, PPP2R2A hemizygous loss correlates with reduced mRNA expression. In contrast, no significant correlation is observed for NKX3.1, a tumor suppressor also located at 8p21.2. Bioinformatics analysis indicates that PPP2R2A may belong to the class of “mutator alterations” occurring early in tumorigenesis that promote driver gene mutations. Indeed, PCa patients with these alterations exhibit reduced disease free progression. PP2A consists of a collection of trimeric holoenzymes whose substrate specificity and function is determined by the regulatory B subunit. There are 14 B subunit genes. While it is well accepted that PP2A plays a key tumor suppressor function in human cells, the particular holoenzyme(s) implicated in different tumor types is unclear. We have found, that limited ectopic expression of B55α in PCa cell lines that naturally express low levels of B55α results in dramatic toxicity. We have linked this to G2/M arrest, without concomitant loss in DNA replication, which leads to euploidy, nuclear enlargement and cell death. Thus, early hemizygous loss of PPP2R2A may facilitate effective mitotic progression. We have also seen that increased expression of B55α in these cells dramatically reduces their tumorigenic potential in SCID mice. Moreover, we observe inhibition in the phosphorylation of PP2A/B55α substrates when B55α activity is reconstituted, including AKT and pRB, suggesting alterations in multiple cancer pathways when B55α is downregulated in tumor cells. Interestingly, treatment of PC3 cells with PP2A activating drugs mimic cell cycle effects seen with B55α reconstitution. Citation Format: Ziran Zhao, Alison kurimchak, Mary Adeyemi, Patrick Woodruff, Vladimir Kolenko, Xavier Graña. Analysis of the tumor suppressor function of B55alpha, the PP2A regulatory subunit encoded by PPP2R2A, in prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3662.
Publication Year: 2016
Publication Date: 2016-07-15
Language: en
Type: article
Indexed In: ['crossref']
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Cited By Count: 1
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