RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding
Background and Aims Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5‐mediating protein (RMP) in an autonomous mouse model of intrahepatic cholan...
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| Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2020-06, Vol.71 (6), p.2005-2022 |
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| container_title | Hepatology (Baltimore, Md.) |
| container_volume | 71 |
| creator | Wan, Zheng‐Hua Jiang, Tian‐Yi Shi, Yuan‐Yuan Pan, Yu‐Fei Lin, Yun‐Kai Ma, Yun‐Han Yang, Chun Feng, Xiao‐Fan Huang, Li‐Feng Kong, Xiao‐Ni Ding, Zhi‐Wen Tan, Ye‐Xiong Dong, Li‐Wei Wang, Hong‐Yang |
| description | Background and Aims
Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5‐mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression.
Approach and Results
RMP‐overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch‐like ECH‐associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP‐KEAP1‐NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis.
Conclusion
These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies. |
| doi_str_mv | 10.1002/hep.30962 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2407757258</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2407757258</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3532-4fbb6a41c423389b8d742ca823f0abdc786391415e5b32335288715f524e97aa3</originalsourceid><addsrcrecordid>eNp1kMtOAjEUhhujUUQXvoBp4srFQK-0s1QEMd4IwbicdGY6UMO02M7EsNJH8Bl9EgdBd67-c3K-fCf5ATjBqIMRIt25XnYointkB7QwJyKilKNd0EJEoCjGND4AhyG8IIRiRuQ-OKCYM8wkboH3yfiSf3183uvcqMrYGRx7V2lj11k2U4D9uVsoOzMuUz4z1pUKTuvSeTPTVgcToLI5vPL1DE7Wa6VspmG6gn1XLvWP8tlUc_gwGRJYOA9vBxdjDC-NzZvbEdgr1CLo4222wdNwMO2PorvH65v-xV2UUU5JxIo07SmGM0YolXEqc8FIpiShBVJpngnZozFmmGue0gbhREqBecEJ07FQirbB2ca79O611qFKXlztbfMyIQwJwQXhsqHON1TmXQheF8nSm1L5VYJRsq46aapOfqpu2NOtsU5Lnf-Rv902QHcDvJmFXv1vSkaD8Ub5DZA0h9g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2407757258</pqid></control><display><type>article</type><title>RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Wan, Zheng‐Hua ; Jiang, Tian‐Yi ; Shi, Yuan‐Yuan ; Pan, Yu‐Fei ; Lin, Yun‐Kai ; Ma, Yun‐Han ; Yang, Chun ; Feng, Xiao‐Fan ; Huang, Li‐Feng ; Kong, Xiao‐Ni ; Ding, Zhi‐Wen ; Tan, Ye‐Xiong ; Dong, Li‐Wei ; Wang, Hong‐Yang</creator><creatorcontrib>Wan, Zheng‐Hua ; Jiang, Tian‐Yi ; Shi, Yuan‐Yuan ; Pan, Yu‐Fei ; Lin, Yun‐Kai ; Ma, Yun‐Han ; Yang, Chun ; Feng, Xiao‐Fan ; Huang, Li‐Feng ; Kong, Xiao‐Ni ; Ding, Zhi‐Wen ; Tan, Ye‐Xiong ; Dong, Li‐Wei ; Wang, Hong‐Yang</creatorcontrib><description>Background and Aims
Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5‐mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression.
Approach and Results
RMP‐overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch‐like ECH‐associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP‐KEAP1‐NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis.
Conclusion
These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.30962</identifier><identifier>PMID: 31541481</identifier><language>eng</language><publisher>United States: Wolters Kluwer Health, Inc</publisher><subject>Animals ; Antioxidants ; Apoptosis ; Carcinogenesis - drug effects ; Carcinogenesis - metabolism ; Cell Line ; Cell survival ; Cell Transformation, Neoplastic - metabolism ; Cholangiocarcinoma ; Cholangiocarcinoma - metabolism ; Cholangiocarcinoma - pathology ; Competition ; Drug resistance ; Drug Resistance, Neoplasm ; Hepatology ; Humans ; Kelch-Like ECH-Associated Protein 1 - metabolism ; Medical prognosis ; Metastases ; Mice ; NF-E2-Related Factor 2 - metabolism ; Nuclear transport ; Oxidative Stress ; Proteins ; Reactive oxygen species ; Repressor Proteins - metabolism ; Tumor cells ; Tumorigenesis ; Ubiquitination</subject><ispartof>Hepatology (Baltimore, Md.), 2020-06, Vol.71 (6), p.2005-2022</ispartof><rights>2019 by the American Association for the Study of Liver Diseases.</rights><rights>2020 by the American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3532-4fbb6a41c423389b8d742ca823f0abdc786391415e5b32335288715f524e97aa3</citedby><cites>FETCH-LOGICAL-c3532-4fbb6a41c423389b8d742ca823f0abdc786391415e5b32335288715f524e97aa3</cites><orcidid>0000-0002-1406-051X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.30962$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.30962$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,777,781,1412,27905,27906,45555,45556</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31541481$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wan, Zheng‐Hua</creatorcontrib><creatorcontrib>Jiang, Tian‐Yi</creatorcontrib><creatorcontrib>Shi, Yuan‐Yuan</creatorcontrib><creatorcontrib>Pan, Yu‐Fei</creatorcontrib><creatorcontrib>Lin, Yun‐Kai</creatorcontrib><creatorcontrib>Ma, Yun‐Han</creatorcontrib><creatorcontrib>Yang, Chun</creatorcontrib><creatorcontrib>Feng, Xiao‐Fan</creatorcontrib><creatorcontrib>Huang, Li‐Feng</creatorcontrib><creatorcontrib>Kong, Xiao‐Ni</creatorcontrib><creatorcontrib>Ding, Zhi‐Wen</creatorcontrib><creatorcontrib>Tan, Ye‐Xiong</creatorcontrib><creatorcontrib>Dong, Li‐Wei</creatorcontrib><creatorcontrib>Wang, Hong‐Yang</creatorcontrib><title>RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Background and Aims
Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5‐mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression.
Approach and Results
RMP‐overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch‐like ECH‐associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP‐KEAP1‐NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis.
Conclusion
These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.</description><subject>Animals</subject><subject>Antioxidants</subject><subject>Apoptosis</subject><subject>Carcinogenesis - drug effects</subject><subject>Carcinogenesis - metabolism</subject><subject>Cell Line</subject><subject>Cell survival</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cholangiocarcinoma</subject><subject>Cholangiocarcinoma - metabolism</subject><subject>Cholangiocarcinoma - pathology</subject><subject>Competition</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Kelch-Like ECH-Associated Protein 1 - metabolism</subject><subject>Medical prognosis</subject><subject>Metastases</subject><subject>Mice</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Nuclear transport</subject><subject>Oxidative Stress</subject><subject>Proteins</subject><subject>Reactive oxygen species</subject><subject>Repressor Proteins - metabolism</subject><subject>Tumor cells</subject><subject>Tumorigenesis</subject><subject>Ubiquitination</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMtOAjEUhhujUUQXvoBp4srFQK-0s1QEMd4IwbicdGY6UMO02M7EsNJH8Bl9EgdBd67-c3K-fCf5ATjBqIMRIt25XnYointkB7QwJyKilKNd0EJEoCjGND4AhyG8IIRiRuQ-OKCYM8wkboH3yfiSf3183uvcqMrYGRx7V2lj11k2U4D9uVsoOzMuUz4z1pUKTuvSeTPTVgcToLI5vPL1DE7Wa6VspmG6gn1XLvWP8tlUc_gwGRJYOA9vBxdjDC-NzZvbEdgr1CLo4222wdNwMO2PorvH65v-xV2UUU5JxIo07SmGM0YolXEqc8FIpiShBVJpngnZozFmmGue0gbhREqBecEJ07FQirbB2ca79O611qFKXlztbfMyIQwJwQXhsqHON1TmXQheF8nSm1L5VYJRsq46aapOfqpu2NOtsU5Lnf-Rv902QHcDvJmFXv1vSkaD8Ub5DZA0h9g</recordid><startdate>202006</startdate><enddate>202006</enddate><creator>Wan, Zheng‐Hua</creator><creator>Jiang, Tian‐Yi</creator><creator>Shi, Yuan‐Yuan</creator><creator>Pan, Yu‐Fei</creator><creator>Lin, Yun‐Kai</creator><creator>Ma, Yun‐Han</creator><creator>Yang, Chun</creator><creator>Feng, Xiao‐Fan</creator><creator>Huang, Li‐Feng</creator><creator>Kong, Xiao‐Ni</creator><creator>Ding, Zhi‐Wen</creator><creator>Tan, Ye‐Xiong</creator><creator>Dong, Li‐Wei</creator><creator>Wang, Hong‐Yang</creator><general>Wolters Kluwer Health, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><orcidid>https://orcid.org/0000-0002-1406-051X</orcidid></search><sort><creationdate>202006</creationdate><title>RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding</title><author>Wan, Zheng‐Hua ; 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Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is regulated primarily by NRF2 during tumorigenesis. Here, we demonstrate that deletion of RBP5‐mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression.
Approach and Results
RMP‐overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 (Kelch‐like ECH‐associated protein 1) through the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP‐KEAP1‐NRF2 axis promotes ICC tumorigenesis, metastasis, and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis.
Conclusion
These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.</abstract><cop>United States</cop><pub>Wolters Kluwer Health, Inc</pub><pmid>31541481</pmid><doi>10.1002/hep.30962</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-1406-051X</orcidid></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Antioxidants Apoptosis Carcinogenesis - drug effects Carcinogenesis - metabolism Cell Line Cell survival Cell Transformation, Neoplastic - metabolism Cholangiocarcinoma Cholangiocarcinoma - metabolism Cholangiocarcinoma - pathology Competition Drug resistance Drug Resistance, Neoplasm Hepatology Humans Kelch-Like ECH-Associated Protein 1 - metabolism Medical prognosis Metastases Mice NF-E2-Related Factor 2 - metabolism Nuclear transport Oxidative Stress Proteins Reactive oxygen species Repressor Proteins - metabolism Tumor cells Tumorigenesis Ubiquitination |
| title | RPB5‐Mediating Protein Promotes Cholangiocarcinoma Tumorigenesis and Drug Resistance by Competing With NRF2 for KEAP1 Binding |
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