Targeting survivin by a novel small molecule inhibitor, YM155 induces autophagic cell death in human breast cancer cells

• Main Authors: Chih-YunLiu, 劉知耘
• Other Authors: Chun Hei Antonio Cheung
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/24942197536310680653

碩士 === 國立成功大學 === 藥理學研究所 === 101 === Despite hormone therapy, targeted therapy and chemotherapy have been developed to target different types of breast cancer; the current breast cancer treatments still have several limitations and undesired side-effects. Thus, it is important to develop novel strategies to treat breast cancer. Survivin (BIRC5) is a member of the inhibitor-of-apoptosis proteins family, and it has been shown to play important role in breast cancer development and progression. YM155 is a novel small molecule inhibitor of survivin. Despite YM155 is currently undergoing different phase II clinical trials including studies in patients with breast cancer, its effectiveness in targeting the estrogen receptor (ER) positive Tamoxifen-resistant breast cancer was seldom determined in the past. In addition, it is still unclear whether YM155 exhibits differential anti-breast cancer functions in different breast cancer subtypes. The purpose of this study is to determine the effectiveness of YM155 in targeting various types of breast cancer and its differential molecular mechanism of action in different breast cancer cell lines. Here, YM155 is equally effective in targeting both the parental ER-positive Tamoxifen-sensitive MCF7 and the MCF7-dervided ER-positive Tamoxifen-resistant breast cancer cells in vitro. YM155 is also effective in targeting the triple-negative MDA-MB-231 breast cancer cells. Surprisingly, Western blot analysis, immunofluorescent microscopy and autophagy/apoptosis inhibition assay revealed that targeting survivin by YM155 induced autophagic cell death, but not caspase-3 dependent apoptosis, in most of the tested breast cancer cell lines; despite it is widely believed that survivin inhibits apoptosis through physical interactions with caspase-3. Interestingly, YM155 also induced autophagy-dependent DNA damage in the treated breast cancer cells. Taken together, targeting survivin by YM155 induces autophagic cell death in breast cancer cells. Importantly, YM155 is a promising anti-cancer compound that has potential for the management of various types of breast cancer.