Research Papers:
Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation
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Abstract
Yu Ran Lee1, Ki Mo Kim2, Byeong Hwa Jeon1, Sunga Choi1
1Research Institute of Medical Sciences, Department of Physiology, School of Medicine, Chungnam National University, Daejeon, 301747, Korea
2Cancer Research Team, Korean Medicine Based Herbal Drug Research Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, (KIOM), Daejeon, 305811, Korea
Correspondence to:
Byeong Hwa Jeon, e-mail: [email protected]
Sunga Choi, e-mail: [email protected]
Keywords: triple-negative breast cancer, acetylation, apoptosis, RAGE, APE1/Ref-1
Received: April 14, 2015 Accepted: June 12, 2015 Published: June 23, 2015
ABSTRACT
The present study evaluated the mechanism of apoptosis caused by post-translational modification, hyperacetylation in triple-negative breast cancer (TNBC) cells. We previously showed that trichostatin A (TSA) induced secretion of acetylated apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1). This is the first report showing that Ac-APE1/Ref-1 initiates apoptosis in TNBC cells by binding to the receptor for advanced glycation end products (RAGE). The functional significance of secreted Ac-APE1/Ref-1 was studied by induction of intracellular hyperacetylation through co-treatment with acetylsalicylic acid and TSA in MDA-MB-231 cells. In response to hyperacetylation, secretion of Ac-APE1/Ref-1 in vesicles was observed, resulting in significantly decreased cell viability and induction of apoptosis with increased expression of RAGE. The hyperacetylation-induced apoptosis was similar in two other TNBC cell lines: BT-459 and MDA-MB-468. Therefore, hyperacetylation may be a therapeutic target for treatment of TNBCs. This study introduces a novel paradigm whereby post-translational modification induces apoptotic cell death in breast cancer cells resistant to standard chemotherapeutic agents through secretion of auto- or paracrine molecules such as Ac-APE1/Ref-1.
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