Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation

Yu Ran Lee,Byeong Hwa Jeon,Sunga Choi,Ki Mo Kim

doi:10.18632/oncotarget.4345

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.

Highlights

Breast cancer is the most prevalent cancer in women worldwide
The present study provides compelling experimental evidence to indicate that the stimulation of apoptosis by the binding of secreted Ac-APE1/Ref-1 with receptor for advanced glycation end products (RAGE) is essential for the death of hyperacetylated triple-negative breast cancer (TNBC) cells
To investigate the potential for cell death to be regulated by acetylation, we determined the effect of co-treatment with acetylsalicylic acid (ASA) and trichostatin A (TSA) on cell viability in MDAMB-231 and MCF-7 human breast cancer cell lines

Summary

Introduction

The incidence of breast cancer is increasing and 1.7 million new cases were diagnosed in 2012 [1]. Hormone-related factors that reflect exposure to estrogen and progesterone can be derived from family history, atypical hyperplasia of the breast, early age at menarche, nulliparity, delayed childbearing, and late menopause [4, 5]. These factors are associated with an increased incidence of breast cancers that express ER and PR, but not with breast cancers lacking expression of these receptors [6, 7]. Breast cancers with HER2/neu are much more aggressive and fast-growing and can be treated with Herceptin or Tykerb, which inhibit HER2/neu-mediated signaling [12, 13]

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