Ribonucleotide reductase subunit M2B deficiency leads to mitochondrial permeability transition pore opening and is associated with aggressive clinicopathologic manifestations of breast cancer

Lijun Xue, Xiyong Liu, Qinchuan Wang, Charlie Q. Liu, Yunru Chen, Wei Jia, Ronhong Hsie, Yifan Chen, Frank Luh, Shu Zheng, Yun Yen

研究成果: 雜誌貢獻文章

摘要

Ribonucleotide reductase small subunit M2B (RRM2B) plays an essential role in maintaining mitochondrial homeostasis. Mitochondrial permeability transition pore (MPTP) is a key regulator of mitochondrial homeostasis. MPTP contributes to cell death and is crucial in cancer progression. RRM2B’s relation to MPTP is not well known, and the role of RRM2B in cancer progression is controversial. Here, our aim was to study the role of RRM2B in regulating MPTP and the association between RRM2B and clinicopathological manifestations in breast cancer. Analysis of Rrm2b-/-mice cells found changes consistent with MPTP opening, including mitochondrial swelling and upregulation of cyclophilin D (CypD), a protein that activates MPTP opening. Silencing of RRM2B gene expression in MCF7 and KB cell lines led to MPTP opening. Accordingly, dysfunctional oxidative phosphorylation and elevated superoxide levels were also detected in RRM2B-silenced MCF7 and KB cell lines, which was consistent with the findings by gene set enrichment analysis of 159 breast cancer cases that genes involving respiratory electron transport were enriched in high-RRM2B breast cancer, and genes involving biologic oxidation were enriched in low-RRM2B breast cancers. A metabolomic study revealed that spermine levels in RRM2B-silenced MCF7 and KB cells were only 5% and 8% of control levels, respectively. Addition of exogenous spermine to RRM2B-silenced MCF7 and KB cells was able to reverse the MPTP opening induced by RRM2B deficiency. These results suggest that RRM2B may induce MPTP opening through reducing spermine levels. Immunohistochemical analysis of 148 breast cancer cases showed that RRM2B and CypD protein levels were inversely correlated in breast cancer specimens (P<0.05), so were their associated clinicopathologic parameters that high-level RRM2B expression was associated with better clinicopathological features. We conclude that RRM2B deficiency leads to MPTP opening mediated by spermine. Coupling of low RRM2B and high CypD expression is associated with aggressive manifestations of breast cancer.
原文英語
文章編號AJTR0084684
頁(從 - 到)3635-3649
頁數15
期刊American Journal of Translational Research
10
發行號11
出版狀態已發佈 - 一月 1 2018

指紋

Ribonucleotide Reductases
Breast Neoplasms
KB Cells
Spermine
MCF-7 Cells
mitochondrial permeability transition pore
Genes
Neoplasm Genes
Respiratory Transport
Homeostasis
Cells
Mitochondrial Swelling
Cell Line
Metabolomics
Oxidative Phosphorylation
Level control
Cell death

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research

引用此文

Ribonucleotide reductase subunit M2B deficiency leads to mitochondrial permeability transition pore opening and is associated with aggressive clinicopathologic manifestations of breast cancer. / Xue, Lijun; Liu, Xiyong; Wang, Qinchuan; Liu, Charlie Q.; Chen, Yunru; Jia, Wei; Hsie, Ronhong; Chen, Yifan; Luh, Frank; Zheng, Shu; Yen, Yun.

於: American Journal of Translational Research, 卷 10, 編號 11, AJTR0084684, 01.01.2018, p. 3635-3649.

研究成果: 雜誌貢獻文章

Xue, Lijun ; Liu, Xiyong ; Wang, Qinchuan ; Liu, Charlie Q. ; Chen, Yunru ; Jia, Wei ; Hsie, Ronhong ; Chen, Yifan ; Luh, Frank ; Zheng, Shu ; Yen, Yun. / Ribonucleotide reductase subunit M2B deficiency leads to mitochondrial permeability transition pore opening and is associated with aggressive clinicopathologic manifestations of breast cancer. 於: American Journal of Translational Research. 2018 ; 卷 10, 編號 11. 頁 3635-3649.
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abstract = "Ribonucleotide reductase small subunit M2B (RRM2B) plays an essential role in maintaining mitochondrial homeostasis. Mitochondrial permeability transition pore (MPTP) is a key regulator of mitochondrial homeostasis. MPTP contributes to cell death and is crucial in cancer progression. RRM2B’s relation to MPTP is not well known, and the role of RRM2B in cancer progression is controversial. Here, our aim was to study the role of RRM2B in regulating MPTP and the association between RRM2B and clinicopathological manifestations in breast cancer. Analysis of Rrm2b-/-mice cells found changes consistent with MPTP opening, including mitochondrial swelling and upregulation of cyclophilin D (CypD), a protein that activates MPTP opening. Silencing of RRM2B gene expression in MCF7 and KB cell lines led to MPTP opening. Accordingly, dysfunctional oxidative phosphorylation and elevated superoxide levels were also detected in RRM2B-silenced MCF7 and KB cell lines, which was consistent with the findings by gene set enrichment analysis of 159 breast cancer cases that genes involving respiratory electron transport were enriched in high-RRM2B breast cancer, and genes involving biologic oxidation were enriched in low-RRM2B breast cancers. A metabolomic study revealed that spermine levels in RRM2B-silenced MCF7 and KB cells were only 5{\%} and 8{\%} of control levels, respectively. Addition of exogenous spermine to RRM2B-silenced MCF7 and KB cells was able to reverse the MPTP opening induced by RRM2B deficiency. These results suggest that RRM2B may induce MPTP opening through reducing spermine levels. Immunohistochemical analysis of 148 breast cancer cases showed that RRM2B and CypD protein levels were inversely correlated in breast cancer specimens (P<0.05), so were their associated clinicopathologic parameters that high-level RRM2B expression was associated with better clinicopathological features. We conclude that RRM2B deficiency leads to MPTP opening mediated by spermine. Coupling of low RRM2B and high CypD expression is associated with aggressive manifestations of breast cancer.",
keywords = "Aggressive manifestations of breast cancer, Cyclophilin D, Mitochondrial permeability transition pore, Ribonucleotide reductase small subunit M2B, Spermine",
author = "Lijun Xue and Xiyong Liu and Qinchuan Wang and Liu, {Charlie Q.} and Yunru Chen and Wei Jia and Ronhong Hsie and Yifan Chen and Frank Luh and Shu Zheng and Yun Yen",
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T1 - Ribonucleotide reductase subunit M2B deficiency leads to mitochondrial permeability transition pore opening and is associated with aggressive clinicopathologic manifestations of breast cancer

AU - Xue, Lijun

AU - Liu, Xiyong

AU - Wang, Qinchuan

AU - Liu, Charlie Q.

AU - Chen, Yunru

AU - Jia, Wei

AU - Hsie, Ronhong

AU - Chen, Yifan

AU - Luh, Frank

AU - Zheng, Shu

AU - Yen, Yun

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Ribonucleotide reductase small subunit M2B (RRM2B) plays an essential role in maintaining mitochondrial homeostasis. Mitochondrial permeability transition pore (MPTP) is a key regulator of mitochondrial homeostasis. MPTP contributes to cell death and is crucial in cancer progression. RRM2B’s relation to MPTP is not well known, and the role of RRM2B in cancer progression is controversial. Here, our aim was to study the role of RRM2B in regulating MPTP and the association between RRM2B and clinicopathological manifestations in breast cancer. Analysis of Rrm2b-/-mice cells found changes consistent with MPTP opening, including mitochondrial swelling and upregulation of cyclophilin D (CypD), a protein that activates MPTP opening. Silencing of RRM2B gene expression in MCF7 and KB cell lines led to MPTP opening. Accordingly, dysfunctional oxidative phosphorylation and elevated superoxide levels were also detected in RRM2B-silenced MCF7 and KB cell lines, which was consistent with the findings by gene set enrichment analysis of 159 breast cancer cases that genes involving respiratory electron transport were enriched in high-RRM2B breast cancer, and genes involving biologic oxidation were enriched in low-RRM2B breast cancers. A metabolomic study revealed that spermine levels in RRM2B-silenced MCF7 and KB cells were only 5% and 8% of control levels, respectively. Addition of exogenous spermine to RRM2B-silenced MCF7 and KB cells was able to reverse the MPTP opening induced by RRM2B deficiency. These results suggest that RRM2B may induce MPTP opening through reducing spermine levels. Immunohistochemical analysis of 148 breast cancer cases showed that RRM2B and CypD protein levels were inversely correlated in breast cancer specimens (P<0.05), so were their associated clinicopathologic parameters that high-level RRM2B expression was associated with better clinicopathological features. We conclude that RRM2B deficiency leads to MPTP opening mediated by spermine. Coupling of low RRM2B and high CypD expression is associated with aggressive manifestations of breast cancer.

AB - Ribonucleotide reductase small subunit M2B (RRM2B) plays an essential role in maintaining mitochondrial homeostasis. Mitochondrial permeability transition pore (MPTP) is a key regulator of mitochondrial homeostasis. MPTP contributes to cell death and is crucial in cancer progression. RRM2B’s relation to MPTP is not well known, and the role of RRM2B in cancer progression is controversial. Here, our aim was to study the role of RRM2B in regulating MPTP and the association between RRM2B and clinicopathological manifestations in breast cancer. Analysis of Rrm2b-/-mice cells found changes consistent with MPTP opening, including mitochondrial swelling and upregulation of cyclophilin D (CypD), a protein that activates MPTP opening. Silencing of RRM2B gene expression in MCF7 and KB cell lines led to MPTP opening. Accordingly, dysfunctional oxidative phosphorylation and elevated superoxide levels were also detected in RRM2B-silenced MCF7 and KB cell lines, which was consistent with the findings by gene set enrichment analysis of 159 breast cancer cases that genes involving respiratory electron transport were enriched in high-RRM2B breast cancer, and genes involving biologic oxidation were enriched in low-RRM2B breast cancers. A metabolomic study revealed that spermine levels in RRM2B-silenced MCF7 and KB cells were only 5% and 8% of control levels, respectively. Addition of exogenous spermine to RRM2B-silenced MCF7 and KB cells was able to reverse the MPTP opening induced by RRM2B deficiency. These results suggest that RRM2B may induce MPTP opening through reducing spermine levels. Immunohistochemical analysis of 148 breast cancer cases showed that RRM2B and CypD protein levels were inversely correlated in breast cancer specimens (P<0.05), so were their associated clinicopathologic parameters that high-level RRM2B expression was associated with better clinicopathological features. We conclude that RRM2B deficiency leads to MPTP opening mediated by spermine. Coupling of low RRM2B and high CypD expression is associated with aggressive manifestations of breast cancer.

KW - Aggressive manifestations of breast cancer

KW - Cyclophilin D

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KW - Ribonucleotide reductase small subunit M2B

KW - Spermine

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