Tis21(/Btg2/Pc3) Triggers Cancer Cell Death, Instead Of Cellular Senescence, By Enhancing Proapoptotic Gene Expression At The Downstream Of P53

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL It has been known that cytoplasmic p53 regulates cell cycle arrest, apoptosis, autophage, and metabolism of human and animal cells in a transactivation-dependent manner. Wild type p53 induces senescence of EJ human bladder cancer cells, which carries oncogenic H-ras and mutant p53. Tumor supporessor, TIS21/BTG2/PC3, is one of the target genes regulated by wild type p53. Employing adenoviral vectors carrying p53(Ad-p53) and TIS21(Ad-TIS21) genes, we investigated effect of TIS21 on cancer cell senescence induced by p53 supplementation; Infection of EJ cells with p53 rapidly induced senescence phenotypes, such as cellular enlargement, inhibition of its growth, expressions of SA-[[Unsupported Character – Symbol Font ]]-galactosidase and SA-pErk1/2, and generation of reactive oxygen species, in addition to down-regulation of PARP and pRb expressions. A mechanism of the senescence was likely to be upregulations of H-ras and paxillin expressions by p53, evidenced by employing si-p53 RNA construct. On the contrary, the combined effect of p53 plus TIS21 significantly induced apoptosis of EJ cells rather than senescence, when evaluated by Annexin V expression, Calcein-AM and EhtD-1 double staining, increased expressions of proapoptotic genes and caspase 3 activity, whereas TIS21 alone failed to induce any changes, as compared with those of the control. p53 plus TIS21 significantly increased Bax and Apaf-1 expressions, whereas paxillin expression was clearly reduced as compared with those of p53 alone. When its mechanism was investigated, acetylation of p53 on K120 and K373 residues were found to be increased in addition to the significant translocation of p53 after coexpression of TIS21. We strongly suggest here that TIS21 is an endogenous cell death promoting gene at the downstream of p53 even in the expressions of oncogenic H-Ras and mutant p53. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 211. doi:10.1158/1538-7445.AM2011-211