Abstract 3112: TIS21BTG2/PC3 enhances down-regulation of c-Myc expression during all-trans-retinoic acid-induced differentiation of acute promyelocytic leukemia cells

Abstract

Abstract c-Myc is a transcription factor that promotes cell growth and proliferation. Deregulated c-myc can induce aberrant proliferation, loss of terminal differentiation and oncogenesis. On the other hand, the 12-O-tetradecanoyl phorbol-13-acetate inducible sequence 21 (TIS21), ortholog of human B-cell translocation gene-2 (BTG2) is an antiproliferative tumor suppressor gene, working as a pan-cell cycle regulator. In this study we have evaluated the effects of all-trans retinoic acid (ATRA) and TIS21BTG2/PC3 on the expression c-Myc in HL-60 promyelocytic leukemia cells, harboring amplified c-myc. We observed that ATRA induced granulocytic differentiation of HL-60 cells as monitored by the expressions of CD11b, CD14, CD38 and microscopic examination of the cells. ATRA treatment led to decrease in cells proliferation accompanied by down-regulation of cyclin D1, cyclin E and cyclin A while up-regulation of p21WAF1 and p27KIP1 and hence G1 phase arrest. Expression of c-Myc was significantly down-regulated during all-trans-retinoic acid induced differentiation, while BTG2TIS21/PC3 was up-regulated (∼2.5 folds). Employing adenovirus carrying TIS21 gene, we observed the slight down regulation of c-Myc expression; TIS21 however, enhanced ATRA-induced differentiation of HL-60 cells to granulocytes and significantly increased down-regulation of c-Myc expression at protein level but mRNA level didn't change. Proteosomal inhibition with MG132 didn't attenuate c-Myc protein levels indicating that ubiquitination/proteosome-mediated proteolysis is not involved in TIS21BTG2/PC3 mediated down-regulation of c-Myc. Inhibition of PI3K/Akt/mTOR pathway with LY294002 however, suggested the possible involvement of TIS21BTG2/PC at least in part through PI3K/Akt/mTOR pathway in regulating c-Myc expression. The present results suggest the modulating effect of TIS21BTG2/PC3 on c-Myc expression in a promyelocytic leukemia cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3112.