title: Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation.
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.
authors.affiliation: Research Institute of Medical Sciences, Department of Physiology, School of Medicine, Chungnam National University, Daejeon, 301747, Korea.
authors.forename: Yu Ran
authors.initials: YR
authors.lastname: Lee
authors.affiliation: Cancer Research Team, Korean Medicine Based Herbal Drug Research Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, (KIOM), Daejeon, 305811, Korea.
authors.forename: Ki Mo
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Research Institute of Medical Sciences, Department of Physiology, School of Medicine, Chungnam National University, Daejeon, 301747, Korea.
authors.forename: Byeong Hwa
authors.initials: BH
authors.lastname: Jeon
authors.affiliation: Research Institute of Medical Sciences, Department of Physiology, School of Medicine, Chungnam National University, Daejeon, 301747, Korea.
authors.forename: Sunga
authors.initials: S
authors.lastname: Choi
mesh_terms: D000107:Acetylation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001241:Aspirin / Q000737:chemistry; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D061986:MCF-7 Cells; D046529:Microscopy, Electron, Transmission; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D006877:Hydroxamic Acids; D000067759:Receptor for Advanced Glycation End Products; C012589:trichostatin A; D048051:p38 Mitogen-Activated Protein Kinases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D001241:Aspirin
keywords: APE1/Ref-1; RAGE; acetylation; apoptosis; triple-negative breast cancer