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

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. A team led by Ho Sup Yoon from the Nanyang Technological University in Singapore has demonstrated an alternative molecular mechanism of the pain reliever aspirin's anti-cancer effect. The team showed that aspirin could inhibit the growth of breast cancer cells by affecting the molecular chaperone FKBP38-mediated stability of the anti-apoptotic protein Bcl-2. Normally, FKBP38 binds Bcl-2 and protects Bcl-2 from degradation. The FKBP38-Bcl-2 binary complex shifts to the mitochondrial membrane, resulting in an inhibition of apoptosis, or programmed cell death. However, aspirin blocks the complex formation between Bcl-2 and FKBP38 and consequently induces the nuclear translocation of a fraction of the cytoplasmic Bcl-2 and its subsequent phosphorylation, leading to the inhibition of cancer cell proliferation and triggers the apoptotic cell death in breast cancer cells. The researchers found that the Bcl-2-overexpressing and estrogen receptor-positive breast cancer cells were particularly susceptible to aspirin.