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Title: Discovering and Characterizing of Survivin Dominant Negative Mutants With Stronger Pro-apoptotic Activity on Cancer Cells and CSCs
Authors: Guo, Wei
Ma, Xingyuan
Fu, Yunhui
Liu, Chang
Liu, Qiuli
Hu, Fabiao
Miao, Hui
Zhang, Tong
Liu, Yuping
Han, Myong Hun
You, Fang 
Yang, Yi
Zheng, Wenyun
Keywords: A549 cells and CSCs
discovering and characterizing
sensitizing chemotherapeutic drugs
stronger pro-apoptotic activity
survivin mutant (TmSm34/84)
Issue Date: 31-Mar-2021
Publisher: Frontiers Media S.A.
Citation: Guo, Wei, Ma, Xingyuan, Fu, Yunhui, Liu, Chang, Liu, Qiuli, Hu, Fabiao, Miao, Hui, Zhang, Tong, Liu, Yuping, Han, Myong Hun, You, Fang, Yang, Yi, Zheng, Wenyun (2021-03-31). Discovering and Characterizing of Survivin Dominant Negative Mutants With Stronger Pro-apoptotic Activity on Cancer Cells and CSCs. Frontiers in Oncology 11 : 635233. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Survivin as a member of the inhibitor of apoptosis proteins (IAPs) family is undetectable in normal cells, but highly expressed in cancer cells and cancer stem cells (CSCs) which makes it an attractive target in cancer therapy. Survivin dominant negative mutants have been reported as competitive inhibitors of endogenous survivin protein in cancer cells. However, there is a lack of systematic comparative studies on which mutants have stronger effect on promoting apoptosis in cancer cells, which will hinder the development of novel anti-cancer drugs. Here, based on the previous study of survivin and its analysis of the relationship between structure and function, we designed and constructed a series of different amino acid mutants from survivin (TmSm34, TmSm48, TmSm84, TmSm34/48, TmSm34/84, and TmSm34/48/84) fused cell-permeable peptide TATm at the N-terminus, and a dominant negative mutant TmSm34/84 with stronger pro-apoptotic activity was selected and evaluated systematically in vitro. The double-site mutant of survivin (TmSm34/84) showed more robust pro-apoptotic activity against A549 cells than others, and could reverse the resistance of A549 CSCs to adriamycin (ADM) (reversal index up to 7.01) by decreasing the expression levels of survivin, P-gp, and Bcl-2 while increasing cleaved caspase-3 in CSCs. This study indicated the selected survivin dominant negative mutant TmSm34/84 is promising to be an excellent candidate for recombinant anti-cancer protein by promoting apoptosis of cancer cells and their stem cells and sensitizing chemotherapeutic drugs. © Copyright © 2021 Guo, Ma, Fu, Liu, Liu, Hu, Miao, Zhang, Liu, Han, You, Yang and Zheng.
Source Title: Frontiers in Oncology
ISSN: 2234-943X
DOI: 10.3389/fonc.2021.635233
Rights: Attribution 4.0 International
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