Mnsod lysine 68 acetylation leads to cisplatin and doxorubicin resistance due to aberrant mitochondrial metabolism

Yucheng Gao; Yueming Zhu; Elizabeth L. Tran; Valerie Tokars; Angela E. Dean; Songhua Quan; David R Gius

doi:10.7150/ijbs.51184

Mnsod lysine 68 acetylation leads to cisplatin and doxorubicin resistance due to aberrant mitochondrial metabolism

Yucheng Gao, Yueming Zhu, Elizabeth L. Tran, Valerie Tokars, Angela E. Dean, Songhua Quan, David R Gius^*

^*Corresponding author for this work

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

12 Scopus citations

Abstract

Manganese superoxide dismutase (MnSOD) acetylation (Ac) has been shown to be a key posttranslational modification important in the regulation of detoxification activity in various disease models. We have previously demonstrated that MnSOD lysine-68 (K68) acetylation (K68-Ac) leads to a change in function from a superoxide-scavenging homotetramer to a peroxidase-directed monomer. Here, we found that estrogen receptor positive (ER+) breast cancer cell lines (MCF7 and T47D), selected for continuous growth in cisplatin (CDDP) and doxorubicin (DXR), exhibited an increase in MnSODK68-Ac. In addition, MnSOD-K68-Ac, as modeled by the expression of a validated acetylation mimic mutant gene (MnSOD^K68Q), also led to therapy resistance to CDDP and DXR, altered mitochondrial structure and morphology, and aberrant cellular metabolism. MnSOD^K68Q expression in mouse embryo fibroblasts (MEFs) induced an in vitro transformation permissive phenotype. Computerized molecular protein dynamics analysis of both MnSOD-K68-Ac and MnSOD-K68Q exhibited a significant change in charge distribution along the α1 and α2 helices, directly adjacent to the Mn²⁺ binding site, implying that this decrease in surface charge destabilizes tetrameric MnSOD, leading to an enrichment of the monomer. Finally, monomeric MnSOD, as modeled by amber codon substitution to generate MnSODK68-Ac or MnSOD-K68Q expression in mammalian cells, appeared to incorporate Fe to maximally induce its peroxidase activity. In summary, these findings may explain the mechanism behind the observed structural and functional change of MnSOD-K68-Ac.

Original language	English (US)
Pages (from-to)	1203-1216
Number of pages	14
Journal	International Journal of Biological Sciences
Volume	17
Issue number	5
DOIs	https://doi.org/10.7150/ijbs.51184
State	Published - 2021

Funding

DG is supported by R01CA152601, R01 CA253678-01A1, R0 CA214025-04, 1R01CA214025-01, the Avon Foundation for Breast Cancer Research, the Lynn Sage Cancer Research Foundation, the Zell Family Foundation, and the Chicago Biomedical Consortium, as well the Searle Funds at The Chicago Community Trust. YG was supported in part by the Chicago Cancer Baseball Charities at the Lurie Cancer Center of Northwestern University. YZ is supported by a Robert H. Lurie Comprehensive Cancer Center Translation Bridge Fellowship Award. Imaging work was performed at the Northwestern University Center for Advanced Microscopy, which is generously supported by NCI CCSG P30 CA060553, awarded to the Robert H Lurie Comprehensive Cancer Center. The bacterial MnSOD expression and lysine acetylation tRNA mutant plasmids were a kind gift from Dr. Jiangyun Wang, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

Keywords

Acetylation
Acetylome
Aging
Carcinogenesis
Lysine 68
Metabolism
Mitochondria
MnSOD
SIRT3
SOD2
Signaling
Sirtuins

ASJC Scopus subject areas

Applied Microbiology and Biotechnology
Ecology, Evolution, Behavior and Systematics
Molecular Biology
Cell Biology
Developmental Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7150/ijbs.51184

Cite this

@article{5c5780462bb34b49ac5f7f4c70f85c82,

title = "Mnsod lysine 68 acetylation leads to cisplatin and doxorubicin resistance due to aberrant mitochondrial metabolism",

abstract = "Manganese superoxide dismutase (MnSOD) acetylation (Ac) has been shown to be a key posttranslational modification important in the regulation of detoxification activity in various disease models. We have previously demonstrated that MnSOD lysine-68 (K68) acetylation (K68-Ac) leads to a change in function from a superoxide-scavenging homotetramer to a peroxidase-directed monomer. Here, we found that estrogen receptor positive (ER+) breast cancer cell lines (MCF7 and T47D), selected for continuous growth in cisplatin (CDDP) and doxorubicin (DXR), exhibited an increase in MnSODK68-Ac. In addition, MnSOD-K68-Ac, as modeled by the expression of a validated acetylation mimic mutant gene (MnSODK68Q), also led to therapy resistance to CDDP and DXR, altered mitochondrial structure and morphology, and aberrant cellular metabolism. MnSODK68Q expression in mouse embryo fibroblasts (MEFs) induced an in vitro transformation permissive phenotype. Computerized molecular protein dynamics analysis of both MnSOD-K68-Ac and MnSOD-K68Q exhibited a significant change in charge distribution along the α1 and α2 helices, directly adjacent to the Mn2+ binding site, implying that this decrease in surface charge destabilizes tetrameric MnSOD, leading to an enrichment of the monomer. Finally, monomeric MnSOD, as modeled by amber codon substitution to generate MnSODK68-Ac or MnSOD-K68Q expression in mammalian cells, appeared to incorporate Fe to maximally induce its peroxidase activity. In summary, these findings may explain the mechanism behind the observed structural and functional change of MnSOD-K68-Ac.",

keywords = "Acetylation, Acetylome, Aging, Carcinogenesis, Lysine 68, Metabolism, Mitochondria, MnSOD, SIRT3, SOD2, Signaling, Sirtuins",

author = "Yucheng Gao and Yueming Zhu and Tran, {Elizabeth L.} and Valerie Tokars and Dean, {Angela E.} and Songhua Quan and Gius, {David R}",

note = "Funding Information: DG is supported by R01CA152601, R01 CA253678-01A1, R0 CA214025-04, 1R01CA214025-01, the Avon Foundation for Breast Cancer Research, the Lynn Sage Cancer Research Foundation, the Zell Family Foundation, and the Chicago Biomedical Consortium, as well the Searle Funds at The Chicago Community Trust. YG was supported in part by the Chicago Cancer Baseball Charities at the Lurie Cancer Center of Northwestern University. YZ is supported by a Robert H. Lurie Comprehensive Cancer Center Translation Bridge Fellowship Award. Imaging work was performed at the Northwestern University Center for Advanced Microscopy, which is generously supported by NCI CCSG P30 CA060553, awarded to the Robert H Lurie Comprehensive Cancer Center. The bacterial MnSOD expression and lysine acetylation tRNA mutant plasmids were a kind gift from Dr. Jiangyun Wang, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. Publisher Copyright: {\textcopyright} The author(s).",

year = "2021",

doi = "10.7150/ijbs.51184",

language = "English (US)",

volume = "17",

pages = "1203--1216",

journal = "International Journal of Biological Sciences",

issn = "1449-2288",

publisher = "Ivyspring International Publisher",

number = "5",

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TY - JOUR

T1 - Mnsod lysine 68 acetylation leads to cisplatin and doxorubicin resistance due to aberrant mitochondrial metabolism

AU - Gao, Yucheng

AU - Zhu, Yueming

AU - Tran, Elizabeth L.

AU - Tokars, Valerie

AU - Dean, Angela E.

AU - Quan, Songhua

AU - Gius, David R

N1 - Funding Information: DG is supported by R01CA152601, R01 CA253678-01A1, R0 CA214025-04, 1R01CA214025-01, the Avon Foundation for Breast Cancer Research, the Lynn Sage Cancer Research Foundation, the Zell Family Foundation, and the Chicago Biomedical Consortium, as well the Searle Funds at The Chicago Community Trust. YG was supported in part by the Chicago Cancer Baseball Charities at the Lurie Cancer Center of Northwestern University. YZ is supported by a Robert H. Lurie Comprehensive Cancer Center Translation Bridge Fellowship Award. Imaging work was performed at the Northwestern University Center for Advanced Microscopy, which is generously supported by NCI CCSG P30 CA060553, awarded to the Robert H Lurie Comprehensive Cancer Center. The bacterial MnSOD expression and lysine acetylation tRNA mutant plasmids were a kind gift from Dr. Jiangyun Wang, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. Publisher Copyright: © The author(s).

PY - 2021

Y1 - 2021

N2 - Manganese superoxide dismutase (MnSOD) acetylation (Ac) has been shown to be a key posttranslational modification important in the regulation of detoxification activity in various disease models. We have previously demonstrated that MnSOD lysine-68 (K68) acetylation (K68-Ac) leads to a change in function from a superoxide-scavenging homotetramer to a peroxidase-directed monomer. Here, we found that estrogen receptor positive (ER+) breast cancer cell lines (MCF7 and T47D), selected for continuous growth in cisplatin (CDDP) and doxorubicin (DXR), exhibited an increase in MnSODK68-Ac. In addition, MnSOD-K68-Ac, as modeled by the expression of a validated acetylation mimic mutant gene (MnSODK68Q), also led to therapy resistance to CDDP and DXR, altered mitochondrial structure and morphology, and aberrant cellular metabolism. MnSODK68Q expression in mouse embryo fibroblasts (MEFs) induced an in vitro transformation permissive phenotype. Computerized molecular protein dynamics analysis of both MnSOD-K68-Ac and MnSOD-K68Q exhibited a significant change in charge distribution along the α1 and α2 helices, directly adjacent to the Mn2+ binding site, implying that this decrease in surface charge destabilizes tetrameric MnSOD, leading to an enrichment of the monomer. Finally, monomeric MnSOD, as modeled by amber codon substitution to generate MnSODK68-Ac or MnSOD-K68Q expression in mammalian cells, appeared to incorporate Fe to maximally induce its peroxidase activity. In summary, these findings may explain the mechanism behind the observed structural and functional change of MnSOD-K68-Ac.

AB - Manganese superoxide dismutase (MnSOD) acetylation (Ac) has been shown to be a key posttranslational modification important in the regulation of detoxification activity in various disease models. We have previously demonstrated that MnSOD lysine-68 (K68) acetylation (K68-Ac) leads to a change in function from a superoxide-scavenging homotetramer to a peroxidase-directed monomer. Here, we found that estrogen receptor positive (ER+) breast cancer cell lines (MCF7 and T47D), selected for continuous growth in cisplatin (CDDP) and doxorubicin (DXR), exhibited an increase in MnSODK68-Ac. In addition, MnSOD-K68-Ac, as modeled by the expression of a validated acetylation mimic mutant gene (MnSODK68Q), also led to therapy resistance to CDDP and DXR, altered mitochondrial structure and morphology, and aberrant cellular metabolism. MnSODK68Q expression in mouse embryo fibroblasts (MEFs) induced an in vitro transformation permissive phenotype. Computerized molecular protein dynamics analysis of both MnSOD-K68-Ac and MnSOD-K68Q exhibited a significant change in charge distribution along the α1 and α2 helices, directly adjacent to the Mn2+ binding site, implying that this decrease in surface charge destabilizes tetrameric MnSOD, leading to an enrichment of the monomer. Finally, monomeric MnSOD, as modeled by amber codon substitution to generate MnSODK68-Ac or MnSOD-K68Q expression in mammalian cells, appeared to incorporate Fe to maximally induce its peroxidase activity. In summary, these findings may explain the mechanism behind the observed structural and functional change of MnSOD-K68-Ac.

KW - Acetylation

KW - Acetylome

KW - Aging

KW - Carcinogenesis

KW - Lysine 68

KW - Metabolism

KW - Mitochondria

KW - MnSOD

KW - SIRT3

KW - SOD2

KW - Signaling

KW - Sirtuins

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DO - 10.7150/ijbs.51184

M3 - Article

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AN - SCOPUS:85105169772

SN - 1449-2288

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SP - 1203

EP - 1216

JO - International Journal of Biological Sciences

JF - International Journal of Biological Sciences

IS - 5

ER -

Mnsod lysine 68 acetylation leads to cisplatin and doxorubicin resistance due to aberrant mitochondrial metabolism

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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