Abstract 3414: Disruption of CREB-CREBBP association by 2-Naphthol AS-E phosphate induces cell cycle arrest and apoptosis in non-small cell lung cancer cells .

Abstract

Abstract The cyclic-AMP response element-binding protein (CREB) plays a critical role in the growth and survival of cancer cells as well as cell metabolism. Our previous studies have shown that enhanced CREB activity correlates with increased growth and survival of non-small cell lung cancer (NSCLC) cell lines. In addition, 2-naphthol AS-E phosphate (NASEp), a small molecule inhibitor of CREB, restricted growth of NSCLC cell lines which was associated with reduced expression of pro-angiogenic factors. NASEp distrupts binding of CREB binding protein (CREBBP) to CREB, however, the mechanism which CREB inhibition by NASEp regulates NSCLC cell growth and survival is not fully understood. Here, we found that NASEp inhibited cell growth, survival, anchorage-independent cell growth and invasion, and also completely blocked the expression of Ki-67 and PCNA, markers of cell proliferation in NSCLC cells. Mechanistically, NASEp caused cell cycle arrest at the sub-G1 or G2 phase through down-regulation of several cyclins (cyclin A2, cyclin B1, cyclin D1 and cyclin E2) and led to apoptosis in NSCLC-derived cell lines. Suppression of cyclin D1 was closely related to decreased expression of activator protein-1 (AP-1). Furthermore, in a murine xenograft model, NASEp significantly reduced tumor burden not only by down-regulating of cyclin E2 and PCNA, but also by induction of apoptosis. Taken together, these results suggest that inhibition of CREB activity through dissociation of CREB-CREBBP by NASEp may be a potent new therapeutic in NSCLC. Citation Format: Jong Woo Lee, Hee Sun Park, Seung-Hee Ryu, Patricia Koch, Julie Boyer, Daniel Morgensztern, Roy S. Herbst, Jaseok Peter Koo. Disruption of CREB-CREBBP association by 2-Naphthol AS-E phosphate induces cell cycle arrest and apoptosis in non-small cell lung cancer cells . [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 3414. doi:10.1158/1538-7445.AM2013-3414