Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation
Mutp53 level is widely variable among individual cancer cells in tumor tissues, and within cells a higher level of mutp53 is usually observed in the nucleus as compared to the cytoplasm. This spatial heterogeneity in mutp53 expression has been well documented and likely plays an important role in tu...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000357 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849770622159159296 |
|---|---|
| author | Liansheng Wang Suqin Zhong Xinru Fan Yuxue Xu Meimei Wang Youcui Xu Yuanyuan Cai Zhong Cao Zhiming Ye Longping Wen Pengfei Wei |
| author_facet | Liansheng Wang Suqin Zhong Xinru Fan Yuxue Xu Meimei Wang Youcui Xu Yuanyuan Cai Zhong Cao Zhiming Ye Longping Wen Pengfei Wei |
| author_sort | Liansheng Wang |
| collection | DOAJ |
| description | Mutp53 level is widely variable among individual cancer cells in tumor tissues, and within cells a higher level of mutp53 is usually observed in the nucleus as compared to the cytoplasm. This spatial heterogeneity in mutp53 expression has been well documented and likely plays an important role in tumor therapeutic resistance. However, its underlying mechanism remains poorly understood.In this study, we first revealed a critical role of micro-environmental reducing status in regulating mutp53 stability and spatially heterogeneous accumulation. Immunofluorescence and ThiolTracker Violet dye staining demonstrated a clear correlation between the cellular mutp53 level and the reducibility in the patient-derived tumor tissues and mutp53-expressing cancer cell lines. The nucleus exhibited both higher reducibility and more mutp53 accumulation than the cytoplasm did. Supplementing GSH exacerbated the accumulation of mutp53, while consuming GSH led to extensive depletion of mutp53, suggesting that the environmental reducing status kept mutp53 stability. Mechanistically, S-glutathionylation could trigger ubiquitination and proteasomal degradation of mutp53. A highly-reducing local environment preserved mutp53 stability by inhibiting glutathionylation and subsequent proteasomal degradation of mutp53, which also provided an explanation for the differential accumulation of mutp53 proteins in the nucleus and cytoplasm. Thirdly, we revealed that the expression level of glutathione reductase (GR) was positively correlated with mutp53 accumulation across the cultured mutp53-expressing cell lines, patient-derived tumor tissues and patient databases. Over-expression of GR reinforced the environmental reducibility, affected glutathionylation and improved mutp53 accumulation, while inhibiting GR either by chemical inhibitors or genetic approach induced massive clearance of a variety of mutp53 and effectively retarded the growth of p53-mutated cell-derived xenografts in mice.These studies provided an explanation for the widely-observed spatial heterogeneous accumulation of mutp53 proteins, and inhibiting GR or directly consuming GSH represented a promising strategy for mutp53 carrying cancer therapy. |
| format | Article |
| id | doaj-art-3af10764ffb84bc68b6fbdc311badf78 |
| institution | DOAJ |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-3af10764ffb84bc68b6fbdc311badf782025-08-20T03:02:56ZengElsevierRedox Biology2213-23172025-04-018110352210.1016/j.redox.2025.103522Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylationLiansheng Wang0Suqin Zhong1Xinru Fan2Yuxue Xu3Meimei Wang4Youcui Xu5Yuanyuan Cai6Zhong Cao7Zhiming Ye8Longping Wen9Pengfei Wei10Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, ChinaGuangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China; School of Medicine & Institute for Life Sciences, South China University of Technology, Guangzhou, 510006, ChinaSchool of Pharmacy, Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, 264003, ChinaSchool of Pharmacy, Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, 264003, China; Yantai Stem Cell and Regenerative Medicine Key Laboratory, Binzhou Medical University, Yantai, 264003, ChinaSchool of Medicine & Institute for Life Sciences, South China University of Technology, Guangzhou, 510006, ChinaGuangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, ChinaSchool of Pharmacy, Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, 264003, ChinaSchool of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, 518107, China; Shenzhen International Institute for Biomedical Research, Silver Star Hi-tech Park, Longhua District, Shenzhen, Guangdong, 518116, ChinaGuangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China; School of Medicine & Institute for Life Sciences, South China University of Technology, Guangzhou, 510006, China; Corresponding author. Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China; Corresponding author.School of Pharmacy, Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, 264003, China; Corresponding author. School of Pharmacy, Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Binzhou Medical University, Yantai, 264003, China.Mutp53 level is widely variable among individual cancer cells in tumor tissues, and within cells a higher level of mutp53 is usually observed in the nucleus as compared to the cytoplasm. This spatial heterogeneity in mutp53 expression has been well documented and likely plays an important role in tumor therapeutic resistance. However, its underlying mechanism remains poorly understood.In this study, we first revealed a critical role of micro-environmental reducing status in regulating mutp53 stability and spatially heterogeneous accumulation. Immunofluorescence and ThiolTracker Violet dye staining demonstrated a clear correlation between the cellular mutp53 level and the reducibility in the patient-derived tumor tissues and mutp53-expressing cancer cell lines. The nucleus exhibited both higher reducibility and more mutp53 accumulation than the cytoplasm did. Supplementing GSH exacerbated the accumulation of mutp53, while consuming GSH led to extensive depletion of mutp53, suggesting that the environmental reducing status kept mutp53 stability. Mechanistically, S-glutathionylation could trigger ubiquitination and proteasomal degradation of mutp53. A highly-reducing local environment preserved mutp53 stability by inhibiting glutathionylation and subsequent proteasomal degradation of mutp53, which also provided an explanation for the differential accumulation of mutp53 proteins in the nucleus and cytoplasm. Thirdly, we revealed that the expression level of glutathione reductase (GR) was positively correlated with mutp53 accumulation across the cultured mutp53-expressing cell lines, patient-derived tumor tissues and patient databases. Over-expression of GR reinforced the environmental reducibility, affected glutathionylation and improved mutp53 accumulation, while inhibiting GR either by chemical inhibitors or genetic approach induced massive clearance of a variety of mutp53 and effectively retarded the growth of p53-mutated cell-derived xenografts in mice.These studies provided an explanation for the widely-observed spatial heterogeneous accumulation of mutp53 proteins, and inhibiting GR or directly consuming GSH represented a promising strategy for mutp53 carrying cancer therapy.http://www.sciencedirect.com/science/article/pii/S2213231725000357Mutant p53GlutathionylationGlutathione reductaseGSH/GSSG ratioUbiquitin-proteasome systemMutant p53-carrying cancer |
| spellingShingle | Liansheng Wang Suqin Zhong Xinru Fan Yuxue Xu Meimei Wang Youcui Xu Yuanyuan Cai Zhong Cao Zhiming Ye Longping Wen Pengfei Wei Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation Redox Biology Mutant p53 Glutathionylation Glutathione reductase GSH/GSSG ratio Ubiquitin-proteasome system Mutant p53-carrying cancer |
| title | Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation |
| title_full | Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation |
| title_fullStr | Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation |
| title_full_unstemmed | Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation |
| title_short | Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation |
| title_sort | glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation |
| topic | Mutant p53 Glutathionylation Glutathione reductase GSH/GSSG ratio Ubiquitin-proteasome system Mutant p53-carrying cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000357 |
| work_keys_str_mv | AT lianshengwang glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT suqinzhong glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT xinrufan glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT yuxuexu glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT meimeiwang glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT youcuixu glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT yuanyuancai glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT zhongcao glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT zhimingye glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT longpingwen glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation AT pengfeiwei glutathionereductaseunderliesthestabilityofmutantp53byantagonizingproteinglutathionylation |