Elucidating respective functions of two domains BIR and C-helix of human IAP survivin for precise targeted regulating mitotic cycle, apoptosis and autophagy of cancer cells
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Fabiao Hu1,*, Daxia Pan1,*, Wenyun Zheng2,*, Ting Yan1, Xiujuan He2, Fuzheng Ren2, Yiming Lu3 and Xingyuan Ma1
1State Key Laboratory of Bioreactor Engineering, and School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China
2Shanghai Key Laboratory of New Drug Design, and School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
3Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
*These authors have contributed equally to this work
Xingyuan Ma, email: [email protected]
Yiming Lu, email: [email protected]
Wenyun Zheng, email: [email protected]
Keywords: BIR and CC domains; survivin; cell cycle; apoptosis and autophagy; breast cancer cells
Received: September 08, 2017 Accepted: November 13, 2017 Published: December 01, 2017
Survivin was the smallest member of the IAP family, which was over expressed in many different cancers, and considered to be a promising hot target for cancer therapy, and our previous study demonstrated that multiple dominant negative mutants from full-length survivin could have many complex effects on cancer cells, such as cell cycle, apoptosis, and autophagy. But it was not yet known what role the two main domains played in those functions, which would be very important for the design of targeted anticancer drugs and for the interpretation of their molecular mechanisms. In this study, based on preparation the two parts (BIR domain and CC domain) of survivin by genetic engineering and cell characterization assay, we discovered that BIR (T34A)-domain peptide could inhibit Bcap-37 cells growth in a dose- and time-dependent manner, increase the proportion of G2/M phase, and induce caspase-dependent apoptosis via the mitochondrial pathway. While CC (T117A)-domain peptide increased the proportion of S-phase cells and increased the level of the autophagy marker protein LC3B significantly. These further experiments confirmed that TAT-BIR (T34A) peptide could be used to inhibit cell proliferation, promote apoptosis, and block mitosis, and TAT-CC (T117A) peptide showed mainly to promote autophagy, process of DNA replication, and mitosis to breast cancer cells. This research will lay the foundation for interpreting the multifunction mechanism of survivin in cell fates, further make senses in developing the anticancer drugs targeting it precisely and efficiently.
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