Abstract 4035: Extracellular secreted Ref-1 triggers triple negative breast cancer cells apoptosis

Abstract

Abstract Triple-negative breast cancers (TNBCs) are most aggressive type and resistant to standard chemotherapy. There is a high demand for developing approaches to treat TNBCs. Recently, some agents inducing post-translational modification (PTM) were suggested to treat therapeutic-resistant cancer cells. We previously discovered that trichostatin A (TSA), histone deacetylase inhibitor (HDACi), - mediated acetylation induced extracellular secretion of the acetylated apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1). This is the first report showing that the Ac-APE1/Ref-1 is not merely a secreted protein but also a signal molecule that plays a critical role in the apoptotic cell death pathway in TNBC. To study the functional significance of the secreted Ac-APE1/Ref-1, we induced PTM, hyperacetylation of intracellular proteins with co-treatment of acetylsalicylic acid (ASA) and TSA in MDA-MB-231 cells. In response to hyperacetylation, the secretion of Ac-APE1/Ref-1 in a form of exosome-like vesicles was observed in both electron microscopy and confocal image analysis. Accordingly, it was caused a statistically significant inhibition of cell viability and induction of apoptotic DNA fragmentation, leading activation of p38 mitogen-activated protein kinase and apoptotic cell death. Blockade of Ac-APE1/Ref-1 thoroughly recovered from the cell death effects. The hyperacetylation-mediated apoptotic cell death was comparably efficient in treatment of another TNBC cell lines, BT549, and MDA-MB-468. Keeping in view secreted APE1/Ref-1 following acetylation - causing apoptotic cell death we suggest that PTM qualifies as an excellent candidate to be exploited for therapeutic agents to treat TNBCs. For future clinical investigations of TNBCs, this study offers a novel paradigm, which stimulation of apoptotic pathway by action of PTM-induced auto- or paracrine signaling molecules is prior to treatment of standard chemotherapeutic resistant cancer cells. Citation Format: Yu Ran Lee, Ki Mo Kim, Hee Kyoung Joo, Byeong Hwa Jeon, Sunga Choi. Extracellular secreted Ref-1 triggers triple negative breast cancer cells apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4035. doi:10.1158/1538-7445.AM2015-4035