Multisite mutation of monomer survivin with enhanced effect on apoptosis regulation of breast cancer cells

Guoying Dai; Wenyun Zheng; Xingyuan Ma; Ping Wang

doi:10.1016/j.biopha.2014.11.015

Multisite mutation of monomer survivin with enhanced effect on apoptosis regulation of breast cancer cells

Guoying Dai, Wenyun Zheng, Xingyuan Ma, Ping Wang

Bioproducts and Biosystems Engineering

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Survivin is an important protein in regulating both cell apoptosis and proliferation. It has attracted growing attentions in recent years as a promising target for cancer therapy. Previous studies have revealed that monomeric survivin regulated apoptosis in a more significant way than the wild-type survivin that generally contains a large portion of its dimers. In order to investigate the roles of monomeric mutant survivin apoptosis and cell cycle regulation of human cancer cells, we developed and tested three dominant-negative mutants with multisite mutations (MSM) including TAT-survivin^34/101/102, TAT-survivin^{34/117/101/102} and TAT-survivin^117/101/102. Results revealed that MSM mutants remained as monomers under ambient conditions, and induced cells (breast cancer Bcap-37 cells) apoptosis even more efficiently, primarily through the caspase-dependent and Bcl-2-related pathways, than non-monomeric mutants. We further identified that the TAT-survivin^34/101/102 and TAT-survivin^117/101/102 MSM significantly inhibited the proliferation of Bcap-37 cells and arrested cells in S and G₂/M phases, while TAT-survivin^{34/117/101/102} arrested cells in G₂/M phase. It appeared to us that TAT-survivin^34/101/102 and TAT-survivin^117/101/102 also inhibited cell proliferation more significantly. These findings suggest that such MSM afford monomeric survivin with promising potentials for cancer therapy.

Original language	English (US)
Pages (from-to)	111-118
Number of pages	8
Journal	Biomedicine and Pharmacotherapy
Volume	69
DOIs	https://doi.org/10.1016/j.biopha.2014.11.015
State	Published - Feb 1 2015

Bibliographical note

Funding Information:
We thank Yanyan Kang for valuable discussion on SEC analysis of survivin mutants. This study was supported by the National Natural Science Foundation ( 30873190; 31471659; 21303050 ), Science and technology innovation action plan of Shanghai ( 14431904300 ) and the National Science Research Project “Significant New Drugs Created” of Eleventh Five-year Plan ( 2009ZX09103-693 ). Dai thanks Chinese Scholarship Council for the support of an international scholarship for visiting research at UMN. Wang thanks sabbatical support from UMN.

Publisher Copyright:
© 2014 Elsevier Masson SAS.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

Keywords

Apoptosis
Breast cancer
Cell cycle regulation
Protein engineering
Site-specific mutagenesis
Survivin

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10.1016/j.biopha.2014.11.015

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@article{cd1117609a034619be954ce3dd7d896e,

title = "Multisite mutation of monomer survivin with enhanced effect on apoptosis regulation of breast cancer cells",

abstract = "Survivin is an important protein in regulating both cell apoptosis and proliferation. It has attracted growing attentions in recent years as a promising target for cancer therapy. Previous studies have revealed that monomeric survivin regulated apoptosis in a more significant way than the wild-type survivin that generally contains a large portion of its dimers. In order to investigate the roles of monomeric mutant survivin apoptosis and cell cycle regulation of human cancer cells, we developed and tested three dominant-negative mutants with multisite mutations (MSM) including TAT-survivin34/101/102, TAT-survivin34/117/101/102 and TAT-survivin117/101/102. Results revealed that MSM mutants remained as monomers under ambient conditions, and induced cells (breast cancer Bcap-37 cells) apoptosis even more efficiently, primarily through the caspase-dependent and Bcl-2-related pathways, than non-monomeric mutants. We further identified that the TAT-survivin34/101/102 and TAT-survivin117/101/102 MSM significantly inhibited the proliferation of Bcap-37 cells and arrested cells in S and G2/M phases, while TAT-survivin34/117/101/102 arrested cells in G2/M phase. It appeared to us that TAT-survivin34/101/102 and TAT-survivin117/101/102 also inhibited cell proliferation more significantly. These findings suggest that such MSM afford monomeric survivin with promising potentials for cancer therapy.",

keywords = "Apoptosis, Breast cancer, Cell cycle regulation, Protein engineering, Site-specific mutagenesis, Survivin",

author = "Guoying Dai and Wenyun Zheng and Xingyuan Ma and Ping Wang",

note = "Funding Information: We thank Yanyan Kang for valuable discussion on SEC analysis of survivin mutants. This study was supported by the National Natural Science Foundation ( 30873190; 31471659; 21303050 ), Science and technology innovation action plan of Shanghai ( 14431904300 ) and the National Science Research Project “Significant New Drugs Created” of Eleventh Five-year Plan ( 2009ZX09103-693 ). Dai thanks Chinese Scholarship Council for the support of an international scholarship for visiting research at UMN. Wang thanks sabbatical support from UMN. Publisher Copyright: {\textcopyright} 2014 Elsevier Masson SAS. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.",

year = "2015",

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day = "1",

doi = "10.1016/j.biopha.2014.11.015",

language = "English (US)",

volume = "69",

pages = "111--118",

journal = "Biomedicine and Pharmacotherapy",

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T1 - Multisite mutation of monomer survivin with enhanced effect on apoptosis regulation of breast cancer cells

AU - Dai, Guoying

AU - Zheng, Wenyun

AU - Ma, Xingyuan

AU - Wang, Ping

N1 - Funding Information: We thank Yanyan Kang for valuable discussion on SEC analysis of survivin mutants. This study was supported by the National Natural Science Foundation ( 30873190; 31471659; 21303050 ), Science and technology innovation action plan of Shanghai ( 14431904300 ) and the National Science Research Project “Significant New Drugs Created” of Eleventh Five-year Plan ( 2009ZX09103-693 ). Dai thanks Chinese Scholarship Council for the support of an international scholarship for visiting research at UMN. Wang thanks sabbatical support from UMN. Publisher Copyright: © 2014 Elsevier Masson SAS. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - Survivin is an important protein in regulating both cell apoptosis and proliferation. It has attracted growing attentions in recent years as a promising target for cancer therapy. Previous studies have revealed that monomeric survivin regulated apoptosis in a more significant way than the wild-type survivin that generally contains a large portion of its dimers. In order to investigate the roles of monomeric mutant survivin apoptosis and cell cycle regulation of human cancer cells, we developed and tested three dominant-negative mutants with multisite mutations (MSM) including TAT-survivin34/101/102, TAT-survivin34/117/101/102 and TAT-survivin117/101/102. Results revealed that MSM mutants remained as monomers under ambient conditions, and induced cells (breast cancer Bcap-37 cells) apoptosis even more efficiently, primarily through the caspase-dependent and Bcl-2-related pathways, than non-monomeric mutants. We further identified that the TAT-survivin34/101/102 and TAT-survivin117/101/102 MSM significantly inhibited the proliferation of Bcap-37 cells and arrested cells in S and G2/M phases, while TAT-survivin34/117/101/102 arrested cells in G2/M phase. It appeared to us that TAT-survivin34/101/102 and TAT-survivin117/101/102 also inhibited cell proliferation more significantly. These findings suggest that such MSM afford monomeric survivin with promising potentials for cancer therapy.

AB - Survivin is an important protein in regulating both cell apoptosis and proliferation. It has attracted growing attentions in recent years as a promising target for cancer therapy. Previous studies have revealed that monomeric survivin regulated apoptosis in a more significant way than the wild-type survivin that generally contains a large portion of its dimers. In order to investigate the roles of monomeric mutant survivin apoptosis and cell cycle regulation of human cancer cells, we developed and tested three dominant-negative mutants with multisite mutations (MSM) including TAT-survivin34/101/102, TAT-survivin34/117/101/102 and TAT-survivin117/101/102. Results revealed that MSM mutants remained as monomers under ambient conditions, and induced cells (breast cancer Bcap-37 cells) apoptosis even more efficiently, primarily through the caspase-dependent and Bcl-2-related pathways, than non-monomeric mutants. We further identified that the TAT-survivin34/101/102 and TAT-survivin117/101/102 MSM significantly inhibited the proliferation of Bcap-37 cells and arrested cells in S and G2/M phases, while TAT-survivin34/117/101/102 arrested cells in G2/M phase. It appeared to us that TAT-survivin34/101/102 and TAT-survivin117/101/102 also inhibited cell proliferation more significantly. These findings suggest that such MSM afford monomeric survivin with promising potentials for cancer therapy.

KW - Apoptosis

KW - Breast cancer

KW - Cell cycle regulation

KW - Protein engineering

KW - Site-specific mutagenesis

KW - Survivin

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DO - 10.1016/j.biopha.2014.11.015

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C2 - 25661346

AN - SCOPUS:84922252106

VL - 69

SP - 111

EP - 118

JO - Biomedicine and Pharmacotherapy

JF - Biomedicine and Pharmacotherapy

SN - 0753-3322

ER -

Multisite mutation of monomer survivin with enhanced effect on apoptosis regulation of breast cancer cells

Abstract

Bibliographical note

Keywords

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