The signal transduction of Annonacin-induced cell growth arrest and apoptosis in breast cancer MCF-7 cells

• Main Authors: Yu-Min Ko, 柯佑民
• Other Authors: Lea-Yea Chuang
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/92929768449630174743

博士 === 高雄醫學大學 === 醫學研究所 === 101 === Tamoxifen is effective in breast cancer patients with positive estrogen receptor α (ERα), which is present in 50-80% of breast cancer patients. Because those patients who were treated with tamoxifen acquired drug resistance and often retained at relapse and that the estrogen receptor was functional. Recent studies also demonstrate that overexpression of SIRT1 and activation of AKT/mTOR pathway were related with resistance to endocrine therapy and a worse outcome in ERα positive breast cancer patients. Pawpaw and soursop are anticancer annonaceous plants in complementary mediceine. Thus, we studied the effects of annonacin, an annonaceous aceogenin, in breast cancer. In this study, we found that in ERα-positive MCF-7 cells, annonacin and 4-hydoxytamoxifen decreased cell survival whereas annonacin increased cell death at 48 hours. Annonacin and 4-hydoxytamoxifen were additive in inhibiting cell survival. Annonacin induced G0/G1 growth arrest while increasing p21WAF1 and p27kip1 and decreasing cyclin D1 protein expression. Annonacin increased apoptosis while decreasing Bcl-2 protein expression. The combination of annonacin and 4-hydoxytamoxifen decreased Bcl-2 protein expression and ERα bioactivity more than annonacin did alone. Annonacin, but not 4-hydroxytamoxifen, decreased ERα protein expression. Moreover, annonacin decreased phosphorylation of ERK1/2, JNK and STAT3. We also found that in ERα positive MCF-7 cells, annonacin decreased SIRT1 expression and inhibited SIRT1 bioactivity to increase p53 expression and acetylation form. Annonacin also caused MCF-7 apoaptosis via increased p53-induced apoptosis protein, PUMA, PARP, and caspase 9. Moreover, we also indicated anonnacin inhibited AKT/mTOR pathway by decreased mTOR and AKT total protein and phosphorylation type.Annonacin also decreased AKT/mTOR signaling molecules, S6K, protein expression and phosphorylation, so that resulted to decreased cylcin D1 protein expression and Bad protein phosphorylation to arrest cell cycle and apoptosis. In nude mice, annonacin decreased MCF-7 xenograft tumor size at 7-22 days. Moreover, annonacin decreased ERα, cyclin D1, Bcl-2, SIRT1, mTOR and AKT protein expression in the xenograft at 22 days.