Aspirin-induced Bcl-2 translocation and its phosphorylation in the nucleus trigger apoptosis in breast cancer cells

Bo-Hwa Choi,Ho Sup Yoon,Kwanghee Baek,Goutam Chakraborty

doi:10.1038/emm.2013.91

Abstract

Here, we report that B-cell lymphoma 2 (Bcl-2) is a novel target molecule of aspirin in breast cancer cells. Aspirin influenced the formation of a complex by Bcl-2 and FKBP38 and induced the nuclear translocation of Bcl-2 and its phosphorylation. These events inhibited cancer cell proliferation and subsequently enhanced MCF-7 breast cancer cell apoptosis. Bcl-2 knockdown using small interfering RNA (siRNA) delayed apoptotic cell death, which correlated with increased proliferation following aspirin exposure. In contrast, Bcl-2 overexpression enhanced the onset of aspirin-induced apoptosis, which was also associated with a significant increase in Bcl-2 phosphorylation in the nucleus. Therefore, this study may provide novel insight into the molecular mechanism of aspirin, particularly its anticancer effects in Bcl-2- and estrogen receptor-positive breast cancer cells.

Highlights

Aspirin, a nonsteroidal anti-inflammatory drug, is a wellknown antipyretic and analgesic agent[1] and is used for the prevention of recurrent transient ischemic attacks or stroke.[2]In addition to its classical anti-inflammatory function, clinical and epidemiological studies have demonstrated that prolonged aspirin use reduces the risk of colorectal, breast, prostate, lung and skin cancers.[3,4,5,6,7] The anticancer effect of aspirin is attributable to its ability to induce apoptosis or inhibit cell proliferation
Aspirin inhibits the interaction of FKBP38 and B-cell lymphoma 2 (Bcl-2) in vitro Molecular docking studies on the interaction of aspirin with FKBP38 (Harikishore A and Yoon HS, unpublished data) led us to examine the effect of aspirin on the association of FKBP38 with Bcl-2
Salicylate is a metabolite of aspirin in cells, but it had no significant effect on the interaction between FKBP38 and Bcl-2 (Figures 1c and e), suggesting that aspirin affected the molecular interaction between FKBP38 and Bcl-2

Summary

Introduction

A nonsteroidal anti-inflammatory drug, is a wellknown antipyretic and analgesic agent[1] and is used for the prevention of recurrent transient ischemic attacks or stroke.[2]In addition to its classical anti-inflammatory function, clinical and epidemiological studies have demonstrated that prolonged aspirin use reduces the risk of colorectal, breast, prostate, lung and skin cancers.[3,4,5,6,7] The anticancer effect of aspirin is attributable to its ability to induce apoptosis or inhibit cell proliferation. The mechanism of aspirin’s therapeutic effects has been established as the irreversible inhibition of cyclooxygenases (COXs) by cross-acetylation.[8]. Overexpression of COX-2 leads to cellular proliferation and angiogenesis and inhibits apoptosis, contributing to carcinogenesis.[9,10] Recent studies have reported COX-2 overexpression in various types of cancers, including colon, lung, breast and head and neck cancers,[11,12,13,14] and it is typically associated with poor prognosis.[15,16] Interestingly, aspirin has been shown to exhibit an antiproliferative effect and to induce apoptosis in a COX-independent manner in colon cancer cells and COX-null mouse embryo fibroblasts.[17,18] the difference in the clinical activities of aspirin at low and high doses cannot explain all the therapeutic effects of aspirin, suggesting that multiple targets might be involved in the biological effects of aspirin

Methods

Results

Conclusion