Abstract 191: Methylseleninic acid super-activates p53 senescence axis as a preventive barrier to prostate tumorigenesis driven by Pten deficiencyin vivo.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Prostate cancer (PCa) arises from progression of pre-invasive lesions such as prostatic intraepithelial neoplasia (PIN) to adenocarcinoma and metastatic disease. Due to the very long latency of lesion progression, chemoprevention of prostate adenocarcinogenesis is recognized as a plausible and essential approach to win the war against PCa. Whereas the results from recent clinical trials (SWOG 9917 and SELECT) did not support the protective function for seleno-methionine (SeMet) supplement in healthy men with or without high grade PIN, we and others have shown that supra-nutritional supplement of methylseleninic acid (MSeA), which differs, both chemically and metabolically, from SeMet, suppressed tumor growth in human prostate cancer xenografts, and in the transgenic adenocarcinoma mouse prostate (TRAMP) model. However, the former models did not mimic primary prevention, and the TRAMP mice vastly differ from the etiology and adenocarcinogenesis nature of the human prostate cancers. Therefore, a mouse model that closely recapitulates the clinic pathological features of human prostate cancer will be essential and necessary to predict the preventive efficacy and mechanisms of MSeA in men. As the loss of tumor suppressor gene Pten (phosphatase and tensin homolog deleted on chromosome 10) plays a causal role in human prostate cancers, the prostate epithelial-specific Pten-knockout mouse is such a preclinical model of choice. Here we utilized Probasin-Cre (Pb-Cre) transgenic mice expressing Cre to delete Pten in prostate epithelium to investigate whether administration of MSeA inhibited prostate tumorigenesis. We treated Pten-knockout and age-matched wild type male mice from 8 weeks of age with water or MSeA at a dose of 3 mg/kg body weight five times a week (Monday through Friday) for 27 weeks and sacrificed them for analyses. Our results show that MSeA significantly suppressed prostate tumorigenesis as evidenced by (1) suppression of tumor progression to high grade PIN or/and adenocarcinoma; (2) a 50% reduction in prostate tumor weight (P<0.01); (3) a significant reduction in cellular proliferation determined by ki67 immunostaining (P<0.01); and (4) attenuation of androgen receptor (AR) signaling. Mechanistically, we found that MSeA induced a super-activation of p53, p21 and cellular senescence. Because intact p53 signaling is preserved in most early prostate lesions, our findings provide compelling rationale to consider MSeA as a bioactive dietary supplement to activate p53-p21 mediated senescence as a barrier to prevent PIN from progressing to advanced prostate cancer. Citation Format: Lei Wang, Hua Xiong, Fengxia Wu, Tao Lin, Junxuan Lu, Yibin Deng. Methylseleninic acid super-activates p53 senescence axis as a preventive barrier to prostate tumorigenesis driven by Pten deficiency in vivo . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 191. doi:10.1158/1538-7445.AM2013-191