Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis
Glioblastoma (GBM), a malignant brain tumor, is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality. Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2022-11, Vol.43 (11), p.2977-2992 |
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| creator | Zheng, Xiang-jin Chen, Wen-lin Yi, Jie Li, Wan Liu, Jin-yi Fu, Wei-qi Ren, Li-wen Li, Sha Ge, Bin-bin Yang, Yi-hui Zhang, Yi-zhi Yang, Hong Du, Guan-hua Wang, Yu Wang, Jin-hua |
| description | Glioblastoma (GBM), a malignant brain tumor, is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality. Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer. In this study we investigated the role of APOC1 in GBM tumorigenesis. Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression. We showed that APOC1 protein expression was markedly increased in four GBM cell lines (U251, U138, A172 and U87) compared to the normal brain glia cell lines (HEB, HA1800). In U251 cells, overexpression of APOC1 promoted cell proliferation, migration, invasion and colony information, which was reversed by APOC1 knockdown. APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice. We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1, promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells. APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase (CBS) expression, which promoted trans-sulfuration and increased GSH synthesis, ultimately leading to an increase in glutathione peroxidase-4 (GPX4). Thus, APOC1 plays a key role in GBM tumorigenesis, conferring resistance to ferroptosis, and may be a promising therapeutic target for GBM. |
| doi_str_mv | 10.1038/s41401-022-00917-3 |
| format | Article |
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Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer. In this study we investigated the role of APOC1 in GBM tumorigenesis. Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression. We showed that APOC1 protein expression was markedly increased in four GBM cell lines (U251, U138, A172 and U87) compared to the normal brain glia cell lines (HEB, HA1800). In U251 cells, overexpression of APOC1 promoted cell proliferation, migration, invasion and colony information, which was reversed by APOC1 knockdown. APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice. We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1, promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells. APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase (CBS) expression, which promoted trans-sulfuration and increased GSH synthesis, ultimately leading to an increase in glutathione peroxidase-4 (GPX4). Thus, APOC1 plays a key role in GBM tumorigenesis, conferring resistance to ferroptosis, and may be a promising therapeutic target for GBM.</description><identifier>ISSN: 1671-4083</identifier><identifier>ISSN: 1745-7254</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/s41401-022-00917-3</identifier><identifier>PMID: 35581292</identifier><language>eng</language><publisher>Singapore: Springer Nature Singapore</publisher><subject>Animals ; Apolipoprotein C-I - metabolism ; Apolipoproteins ; Biomedical and Life Sciences ; Biomedicine ; Brain cancer ; Brain tumors ; Carcinogenesis - metabolism ; Cell Line, Tumor ; Cell migration ; Cell proliferation ; Cell Transformation, Neoplastic ; Cystathionine b-synthase ; Cystathionine beta-Synthase - metabolism ; Ferroptosis ; Gene Expression Regulation, Neoplastic ; Glioblastoma ; Glioblastoma - metabolism ; Glutathione peroxidase ; Humans ; Immunology ; Internal Medicine ; Kelch-Like ECH-Associated Protein 1 - metabolism ; Medical Microbiology ; Mice ; Mice, Nude ; NF-E2-Related Factor 2 - metabolism ; Nuclear transport ; Pharmacology/Toxicology ; Therapeutic targets ; Tumorigenesis ; Vaccine ; Ventricle ; Ventricles (cerebral) ; Xenografts</subject><ispartof>Acta pharmacologica Sinica, 2022-11, Vol.43 (11), p.2977-2992</ispartof><rights>The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2022. corrected publication 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.</rights><rights>The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2022.</rights><rights>The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-34c9e5716f6e40cf7429189a373da53f6dc52208fe1eb6ec29755bc4ebca4bcf3</citedby><cites>FETCH-LOGICAL-c474t-34c9e5716f6e40cf7429189a373da53f6dc52208fe1eb6ec29755bc4ebca4bcf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9622891/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9622891/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35581292$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zheng, Xiang-jin</creatorcontrib><creatorcontrib>Chen, Wen-lin</creatorcontrib><creatorcontrib>Yi, Jie</creatorcontrib><creatorcontrib>Li, Wan</creatorcontrib><creatorcontrib>Liu, Jin-yi</creatorcontrib><creatorcontrib>Fu, Wei-qi</creatorcontrib><creatorcontrib>Ren, Li-wen</creatorcontrib><creatorcontrib>Li, Sha</creatorcontrib><creatorcontrib>Ge, Bin-bin</creatorcontrib><creatorcontrib>Yang, Yi-hui</creatorcontrib><creatorcontrib>Zhang, Yi-zhi</creatorcontrib><creatorcontrib>Yang, Hong</creatorcontrib><creatorcontrib>Du, Guan-hua</creatorcontrib><creatorcontrib>Wang, Yu</creatorcontrib><creatorcontrib>Wang, Jin-hua</creatorcontrib><title>Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacol Sin</addtitle><description>Glioblastoma (GBM), a malignant brain tumor, is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality. Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer. In this study we investigated the role of APOC1 in GBM tumorigenesis. Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression. We showed that APOC1 protein expression was markedly increased in four GBM cell lines (U251, U138, A172 and U87) compared to the normal brain glia cell lines (HEB, HA1800). In U251 cells, overexpression of APOC1 promoted cell proliferation, migration, invasion and colony information, which was reversed by APOC1 knockdown. APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice. We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1, promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells. APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase (CBS) expression, which promoted trans-sulfuration and increased GSH synthesis, ultimately leading to an increase in glutathione peroxidase-4 (GPX4). Thus, APOC1 plays a key role in GBM tumorigenesis, conferring resistance to ferroptosis, and may be a promising therapeutic target for GBM.</description><subject>Animals</subject><subject>Apolipoprotein C-I - metabolism</subject><subject>Apolipoproteins</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain cancer</subject><subject>Brain tumors</subject><subject>Carcinogenesis - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell proliferation</subject><subject>Cell Transformation, Neoplastic</subject><subject>Cystathionine b-synthase</subject><subject>Cystathionine beta-Synthase - metabolism</subject><subject>Ferroptosis</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Glioblastoma</subject><subject>Glioblastoma - metabolism</subject><subject>Glutathione peroxidase</subject><subject>Humans</subject><subject>Immunology</subject><subject>Internal Medicine</subject><subject>Kelch-Like ECH-Associated Protein 1 - metabolism</subject><subject>Medical Microbiology</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Nuclear transport</subject><subject>Pharmacology/Toxicology</subject><subject>Therapeutic targets</subject><subject>Tumorigenesis</subject><subject>Vaccine</subject><subject>Ventricle</subject><subject>Ventricles (cerebral)</subject><subject>Xenografts</subject><issn>1671-4083</issn><issn>1745-7254</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kUtv1TAQhSNERR_wB1ggS2zYmPrteIN0uWoLagWIx9pynEnwVRKndoLUf4_hlkJZdOWx5jtnZnSq6jklrynh9WkWVBCKCWOYEEM15o-qI6qFxJpJ8bjUSlMsSM0Pq-Ocd4Rwxql5Uh1yKWvKDDuqdps5DmGOc4oLhAltKSrlWD4Z9UOIzeDyEkeHlnWMKfQwQQ4ZNTcoQbv6MPXo8mzziZ5--HzOkJtatH37BSfo18Et0KIOUorzEovoaXXQuSHDs9v3pPp2fvZ1-w5ffbx4v91cYS-0WDAX3oDUVHUKBPGdFszQ2jiueesk71TrJWOk7oBCo8Azo6VsvIDGO9H4jp9Ub_a-89qM0HqYluQGO6cwunRjowv2fmcK320ff1ijGKsNLQavbg1SvF4hL3YM2cMwuAnimi1TSkmhSV0X9OV_6C6uaSrnWaY5EcpowgrF9pRPMecE3d0ylNhfUdp9lLZEaX9HaXkRvfj3jDvJn-wKwPdALq2ph_R39gO2PwHlHKs7</recordid><startdate>20221101</startdate><enddate>20221101</enddate><creator>Zheng, Xiang-jin</creator><creator>Chen, Wen-lin</creator><creator>Yi, Jie</creator><creator>Li, Wan</creator><creator>Liu, Jin-yi</creator><creator>Fu, Wei-qi</creator><creator>Ren, Li-wen</creator><creator>Li, Sha</creator><creator>Ge, Bin-bin</creator><creator>Yang, Yi-hui</creator><creator>Zhang, Yi-zhi</creator><creator>Yang, Hong</creator><creator>Du, Guan-hua</creator><creator>Wang, Yu</creator><creator>Wang, Jin-hua</creator><general>Springer Nature Singapore</general><general>Nature Publishing Group</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>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20221101</creationdate><title>Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis</title><author>Zheng, Xiang-jin ; Chen, Wen-lin ; Yi, Jie ; Li, Wan ; Liu, Jin-yi ; Fu, Wei-qi ; Ren, Li-wen ; Li, Sha ; Ge, Bin-bin ; Yang, Yi-hui ; Zhang, Yi-zhi ; Yang, Hong ; Du, Guan-hua ; Wang, Yu ; Wang, Jin-hua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-34c9e5716f6e40cf7429189a373da53f6dc52208fe1eb6ec29755bc4ebca4bcf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Apolipoprotein C-I - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zheng, Xiang-jin</au><au>Chen, Wen-lin</au><au>Yi, Jie</au><au>Li, Wan</au><au>Liu, Jin-yi</au><au>Fu, Wei-qi</au><au>Ren, Li-wen</au><au>Li, Sha</au><au>Ge, Bin-bin</au><au>Yang, Yi-hui</au><au>Zhang, Yi-zhi</au><au>Yang, Hong</au><au>Du, Guan-hua</au><au>Wang, Yu</au><au>Wang, Jin-hua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacol Sin</addtitle><date>2022-11-01</date><risdate>2022</risdate><volume>43</volume><issue>11</issue><spage>2977</spage><epage>2992</epage><pages>2977-2992</pages><issn>1671-4083</issn><issn>1745-7254</issn><eissn>1745-7254</eissn><abstract>Glioblastoma (GBM), a malignant brain tumor, is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality. Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer. In this study we investigated the role of APOC1 in GBM tumorigenesis. Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression. We showed that APOC1 protein expression was markedly increased in four GBM cell lines (U251, U138, A172 and U87) compared to the normal brain glia cell lines (HEB, HA1800). In U251 cells, overexpression of APOC1 promoted cell proliferation, migration, invasion and colony information, which was reversed by APOC1 knockdown. APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice. We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1, promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells. APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase (CBS) expression, which promoted trans-sulfuration and increased GSH synthesis, ultimately leading to an increase in glutathione peroxidase-4 (GPX4). Thus, APOC1 plays a key role in GBM tumorigenesis, conferring resistance to ferroptosis, and may be a promising therapeutic target for GBM.</abstract><cop>Singapore</cop><pub>Springer Nature Singapore</pub><pmid>35581292</pmid><doi>10.1038/s41401-022-00917-3</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apolipoprotein C-I - metabolism Apolipoproteins Biomedical and Life Sciences Biomedicine Brain cancer Brain tumors Carcinogenesis - metabolism Cell Line, Tumor Cell migration Cell proliferation Cell Transformation, Neoplastic Cystathionine b-synthase Cystathionine beta-Synthase - metabolism Ferroptosis Gene Expression Regulation, Neoplastic Glioblastoma Glioblastoma - metabolism Glutathione peroxidase Humans Immunology Internal Medicine Kelch-Like ECH-Associated Protein 1 - metabolism Medical Microbiology Mice Mice, Nude NF-E2-Related Factor 2 - metabolism Nuclear transport Pharmacology/Toxicology Therapeutic targets Tumorigenesis Vaccine Ventricle Ventricles (cerebral) Xenografts |
| title | Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis |
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