CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3 beta axis
Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma...
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| creator | Mohapatra, Pallavi Shriwas, Omprakash Mohanty, Sibasish Ghosh, Arup Smita, Shuchi Kaushik, Sandeep Rai Arya, Rakesh Rath, Rachna Das Majumdar, Saroj Kumar Muduly, Dillip Kumar Raghav, Sunil K. Nanda, Ranjan K. Dash, Rupesh |
| description | Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatininduced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT-glycogen syntha se kinase-3 beta. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC. |
| doi_str_mv | 10.1172/jci.insight.143643 |
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| fullrecord | <record><control><sourceid>proquest_webof</sourceid><recordid>TN_cdi_webofscience_primary_000621657700019</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_ff7cbbff47654536897a562f50eb8bc2</doaj_id><sourcerecordid>2477499373</sourcerecordid><originalsourceid>FETCH-LOGICAL-c468t-1f8032f463499453ae61305edafdc25d18d73c739e9fea15d3b11a10e1492b3b3</originalsourceid><addsrcrecordid>eNqNUk1v2zAMNYYNa5H1D-ww-DhgcKIvW_ZlQBF0bdF2PSzDjoIkU44Cx8okuVv__ZQ6DdrbThSpx_dIPGbZR4zmGHOy2Gg7t0Ow3TrOMaMVo2-yU0J5U1CO6rcv3ifZWQgbhBDmjKCyfp-dUMoow3V5mqnl3equyltvHyDk2oZdL6Mdcg_BhigHDbl6TFk3PtW7_NcQ86Q6yH6fxbV3Y7dOEfKL7_cFXpzfrBaXP25oriDKXP614UP2zsg-wNkhzrKf3y5Wy6vi9v7yenl-W2hW1bHApkaUGFZR1jSspBIqTFEJrTStJmWL65ZTzWkDjQGJy5YqjCVGgFlDFFV0ll1PvK2TG7Hzdiv9o3DSiqeC852QPlrdgzCGa6WMYbwqk1RVN1yWFTElAlUrTRLX14lrN6ottBqG6GX_ivT1z2DXonMPgjdp_LTDLPt8IPDu9wghiq0NGvpeDuDGIAjjPO1JOU1QMkG1dyF4MEcZjMTea5G8FgevxeR1avr0csBjy7OzCfBlAvwB5UzQFpKXR1i6horgquR8fxdNQtf_j17amG7BDUs3DpH-AwJLyH8</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2477499373</pqid></control><display><type>article</type><title>CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3 beta axis</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /></source><source>PubMed Central</source><creator>Mohapatra, Pallavi ; Shriwas, Omprakash ; Mohanty, Sibasish ; Ghosh, Arup ; Smita, Shuchi ; Kaushik, Sandeep Rai ; Arya, Rakesh ; Rath, Rachna ; Das Majumdar, Saroj Kumar ; Muduly, Dillip Kumar ; Raghav, Sunil K. ; Nanda, Ranjan K. ; Dash, Rupesh</creator><creatorcontrib>Mohapatra, Pallavi ; Shriwas, Omprakash ; Mohanty, Sibasish ; Ghosh, Arup ; Smita, Shuchi ; Kaushik, Sandeep Rai ; Arya, Rakesh ; Rath, Rachna ; Das Majumdar, Saroj Kumar ; Muduly, Dillip Kumar ; Raghav, Sunil K. ; Nanda, Ranjan K. ; Dash, Rupesh</creatorcontrib><description>Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatininduced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT-glycogen syntha se kinase-3 beta. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC.</description><identifier>ISSN: 2379-3708</identifier><identifier>EISSN: 2379-3708</identifier><identifier>DOI: 10.1172/jci.insight.143643</identifier><identifier>PMID: 33434185</identifier><language>eng</language><publisher>ANN ARBOR: Amer Soc Clinical Investigation Inc</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Biomarkers, Tumor - metabolism ; Carcinoma, Squamous Cell - pathology ; Cell biology ; Cell Death ; Cell Line, Tumor ; Cisplatin - pharmacology ; DNA-Binding Proteins - metabolism ; Drug Resistance, Neoplasm - drug effects ; Esophageal Neoplasms - genetics ; Esophageal Squamous Cell Carcinoma - drug therapy ; Esophageal Squamous Cell Carcinoma - genetics ; Gene Expression Regulation, Neoplastic - drug effects ; Glycogen Synthase Kinase 3 beta - genetics ; Glycogen Synthase Kinase 3 beta - metabolism ; Head and Neck Neoplasms - drug therapy ; Head and Neck Neoplasms - genetics ; Humans ; Life Sciences & Biomedicine ; Male ; MARVEL Domain-Containing Proteins ; Medicine, Research & Experimental ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mouth Neoplasms - drug therapy ; Mouth Neoplasms - pathology ; Myelin Proteins - genetics ; Myelin Proteins - metabolism ; Oncology ; Phosphopyruvate Hydratase - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; Research & Experimental Medicine ; Science & Technology ; Squamous Cell Carcinoma of Head and Neck - drug therapy ; Squamous Cell Carcinoma of Head and Neck - genetics ; Tumor Suppressor Proteins - metabolism ; Up-Regulation - drug effects ; Wnt Signaling Pathway - drug effects</subject><ispartof>JCI insight, 2021-02, Vol.6 (4), Article 143643</ispartof><rights>2021 Mohapatra et al. 2021 Mohapatra et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>43</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000621657700019</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c468t-1f8032f463499453ae61305edafdc25d18d73c739e9fea15d3b11a10e1492b3b3</citedby><cites>FETCH-LOGICAL-c468t-1f8032f463499453ae61305edafdc25d18d73c739e9fea15d3b11a10e1492b3b3</cites><orcidid>0000-0003-3259-0124 ; 0000-0002-3463-3522 ; 0000-0003-0981-9293 ; 0000-0003-2089-0891 ; 0000-0002-5418-2212 ; 0000-0001-6427-5714 ; 0000-0001-7151-6539</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934946/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934946/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2104,2116,27931,27932,39265,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33434185$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mohapatra, Pallavi</creatorcontrib><creatorcontrib>Shriwas, Omprakash</creatorcontrib><creatorcontrib>Mohanty, Sibasish</creatorcontrib><creatorcontrib>Ghosh, Arup</creatorcontrib><creatorcontrib>Smita, Shuchi</creatorcontrib><creatorcontrib>Kaushik, Sandeep Rai</creatorcontrib><creatorcontrib>Arya, Rakesh</creatorcontrib><creatorcontrib>Rath, Rachna</creatorcontrib><creatorcontrib>Das Majumdar, Saroj Kumar</creatorcontrib><creatorcontrib>Muduly, Dillip Kumar</creatorcontrib><creatorcontrib>Raghav, Sunil K.</creatorcontrib><creatorcontrib>Nanda, Ranjan K.</creatorcontrib><creatorcontrib>Dash, Rupesh</creatorcontrib><title>CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3 beta axis</title><title>JCI insight</title><addtitle>JCI INSIGHT</addtitle><addtitle>JCI Insight</addtitle><description>Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatininduced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT-glycogen syntha se kinase-3 beta. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Cell biology</subject><subject>Cell Death</subject><subject>Cell Line, Tumor</subject><subject>Cisplatin - pharmacology</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Esophageal Neoplasms - genetics</subject><subject>Esophageal Squamous Cell Carcinoma - drug therapy</subject><subject>Esophageal Squamous Cell Carcinoma - genetics</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Glycogen Synthase Kinase 3 beta - genetics</subject><subject>Glycogen Synthase Kinase 3 beta - metabolism</subject><subject>Head and Neck Neoplasms - drug therapy</subject><subject>Head and Neck Neoplasms - genetics</subject><subject>Humans</subject><subject>Life Sciences & Biomedicine</subject><subject>Male</subject><subject>MARVEL Domain-Containing Proteins</subject><subject>Medicine, Research & Experimental</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Mouth Neoplasms - drug therapy</subject><subject>Mouth Neoplasms - pathology</subject><subject>Myelin Proteins - genetics</subject><subject>Myelin Proteins - metabolism</subject><subject>Oncology</subject><subject>Phosphopyruvate Hydratase - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Research & Experimental Medicine</subject><subject>Science & Technology</subject><subject>Squamous Cell Carcinoma of Head and Neck - drug therapy</subject><subject>Squamous Cell Carcinoma of Head and Neck - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Up-Regulation - drug effects</subject><subject>Wnt Signaling Pathway - drug effects</subject><issn>2379-3708</issn><issn>2379-3708</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqNUk1v2zAMNYYNa5H1D-ww-DhgcKIvW_ZlQBF0bdF2PSzDjoIkU44Cx8okuVv__ZQ6DdrbThSpx_dIPGbZR4zmGHOy2Gg7t0Ow3TrOMaMVo2-yU0J5U1CO6rcv3ifZWQgbhBDmjKCyfp-dUMoow3V5mqnl3equyltvHyDk2oZdL6Mdcg_BhigHDbl6TFk3PtW7_NcQ86Q6yH6fxbV3Y7dOEfKL7_cFXpzfrBaXP25oriDKXP614UP2zsg-wNkhzrKf3y5Wy6vi9v7yenl-W2hW1bHApkaUGFZR1jSspBIqTFEJrTStJmWL65ZTzWkDjQGJy5YqjCVGgFlDFFV0ll1PvK2TG7Hzdiv9o3DSiqeC852QPlrdgzCGa6WMYbwqk1RVN1yWFTElAlUrTRLX14lrN6ottBqG6GX_ivT1z2DXonMPgjdp_LTDLPt8IPDu9wghiq0NGvpeDuDGIAjjPO1JOU1QMkG1dyF4MEcZjMTea5G8FgevxeR1avr0csBjy7OzCfBlAvwB5UzQFpKXR1i6horgquR8fxdNQtf_j17amG7BDUs3DpH-AwJLyH8</recordid><startdate>20210222</startdate><enddate>20210222</enddate><creator>Mohapatra, Pallavi</creator><creator>Shriwas, Omprakash</creator><creator>Mohanty, Sibasish</creator><creator>Ghosh, Arup</creator><creator>Smita, Shuchi</creator><creator>Kaushik, Sandeep Rai</creator><creator>Arya, Rakesh</creator><creator>Rath, Rachna</creator><creator>Das Majumdar, Saroj Kumar</creator><creator>Muduly, Dillip Kumar</creator><creator>Raghav, Sunil K.</creator><creator>Nanda, Ranjan K.</creator><creator>Dash, Rupesh</creator><general>Amer Soc Clinical Investigation Inc</general><general>American Society for Clinical Investigation</general><general>American Society for Clinical investigation</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><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>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-3259-0124</orcidid><orcidid>https://orcid.org/0000-0002-3463-3522</orcidid><orcidid>https://orcid.org/0000-0003-0981-9293</orcidid><orcidid>https://orcid.org/0000-0003-2089-0891</orcidid><orcidid>https://orcid.org/0000-0002-5418-2212</orcidid><orcidid>https://orcid.org/0000-0001-6427-5714</orcidid><orcidid>https://orcid.org/0000-0001-7151-6539</orcidid></search><sort><creationdate>20210222</creationdate><title>CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3 beta axis</title><author>Mohapatra, Pallavi ; Shriwas, Omprakash ; Mohanty, Sibasish ; Ghosh, Arup ; Smita, Shuchi ; Kaushik, Sandeep Rai ; Arya, Rakesh ; Rath, Rachna ; Das Majumdar, Saroj Kumar ; Muduly, Dillip Kumar ; Raghav, Sunil K. ; Nanda, Ranjan K. ; Dash, Rupesh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c468t-1f8032f463499453ae61305edafdc25d18d73c739e9fea15d3b11a10e1492b3b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Cell biology</topic><topic>Cell Death</topic><topic>Cell Line, Tumor</topic><topic>Cisplatin - pharmacology</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Esophageal Neoplasms - genetics</topic><topic>Esophageal Squamous Cell Carcinoma - drug therapy</topic><topic>Esophageal Squamous Cell Carcinoma - genetics</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Glycogen Synthase Kinase 3 beta - genetics</topic><topic>Glycogen Synthase Kinase 3 beta - metabolism</topic><topic>Head and Neck Neoplasms - drug therapy</topic><topic>Head and Neck Neoplasms - genetics</topic><topic>Humans</topic><topic>Life Sciences & Biomedicine</topic><topic>Male</topic><topic>MARVEL Domain-Containing Proteins</topic><topic>Medicine, Research & Experimental</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Mouth Neoplasms - drug therapy</topic><topic>Mouth Neoplasms - pathology</topic><topic>Myelin Proteins - genetics</topic><topic>Myelin Proteins - metabolism</topic><topic>Oncology</topic><topic>Phosphopyruvate Hydratase - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Research & Experimental Medicine</topic><topic>Science & Technology</topic><topic>Squamous Cell Carcinoma of Head and Neck - drug therapy</topic><topic>Squamous Cell Carcinoma of Head and Neck - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Up-Regulation - drug effects</topic><topic>Wnt Signaling Pathway - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mohapatra, Pallavi</creatorcontrib><creatorcontrib>Shriwas, Omprakash</creatorcontrib><creatorcontrib>Mohanty, Sibasish</creatorcontrib><creatorcontrib>Ghosh, Arup</creatorcontrib><creatorcontrib>Smita, Shuchi</creatorcontrib><creatorcontrib>Kaushik, Sandeep Rai</creatorcontrib><creatorcontrib>Arya, Rakesh</creatorcontrib><creatorcontrib>Rath, Rachna</creatorcontrib><creatorcontrib>Das Majumdar, Saroj Kumar</creatorcontrib><creatorcontrib>Muduly, Dillip Kumar</creatorcontrib><creatorcontrib>Raghav, Sunil K.</creatorcontrib><creatorcontrib>Nanda, Ranjan K.</creatorcontrib><creatorcontrib>Dash, Rupesh</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>JCI insight</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mohapatra, Pallavi</au><au>Shriwas, Omprakash</au><au>Mohanty, Sibasish</au><au>Ghosh, Arup</au><au>Smita, Shuchi</au><au>Kaushik, Sandeep Rai</au><au>Arya, Rakesh</au><au>Rath, Rachna</au><au>Das Majumdar, Saroj Kumar</au><au>Muduly, Dillip Kumar</au><au>Raghav, Sunil K.</au><au>Nanda, Ranjan K.</au><au>Dash, Rupesh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3 beta axis</atitle><jtitle>JCI insight</jtitle><stitle>JCI INSIGHT</stitle><addtitle>JCI Insight</addtitle><date>2021-02-22</date><risdate>2021</risdate><volume>6</volume><issue>4</issue><artnum>143643</artnum><issn>2379-3708</issn><eissn>2379-3708</eissn><abstract>Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatininduced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT-glycogen syntha se kinase-3 beta. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC.</abstract><cop>ANN ARBOR</cop><pub>Amer Soc Clinical Investigation Inc</pub><pmid>33434185</pmid><doi>10.1172/jci.insight.143643</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0003-3259-0124</orcidid><orcidid>https://orcid.org/0000-0002-3463-3522</orcidid><orcidid>https://orcid.org/0000-0003-0981-9293</orcidid><orcidid>https://orcid.org/0000-0003-2089-0891</orcidid><orcidid>https://orcid.org/0000-0002-5418-2212</orcidid><orcidid>https://orcid.org/0000-0001-6427-5714</orcidid><orcidid>https://orcid.org/0000-0001-7151-6539</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; PubMed Central |
| subjects | Animals Antineoplastic Agents - pharmacology Apoptosis - drug effects Biomarkers, Tumor - metabolism Carcinoma, Squamous Cell - pathology Cell biology Cell Death Cell Line, Tumor Cisplatin - pharmacology DNA-Binding Proteins - metabolism Drug Resistance, Neoplasm - drug effects Esophageal Neoplasms - genetics Esophageal Squamous Cell Carcinoma - drug therapy Esophageal Squamous Cell Carcinoma - genetics Gene Expression Regulation, Neoplastic - drug effects Glycogen Synthase Kinase 3 beta - genetics Glycogen Synthase Kinase 3 beta - metabolism Head and Neck Neoplasms - drug therapy Head and Neck Neoplasms - genetics Humans Life Sciences & Biomedicine Male MARVEL Domain-Containing Proteins Medicine, Research & Experimental Mice Mice, Inbred BALB C Mice, Nude Mouth Neoplasms - drug therapy Mouth Neoplasms - pathology Myelin Proteins - genetics Myelin Proteins - metabolism Oncology Phosphopyruvate Hydratase - metabolism Proto-Oncogene Proteins c-akt - metabolism Research & Experimental Medicine Science & Technology Squamous Cell Carcinoma of Head and Neck - drug therapy Squamous Cell Carcinoma of Head and Neck - genetics Tumor Suppressor Proteins - metabolism Up-Regulation - drug effects Wnt Signaling Pathway - drug effects |
| title | CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3 beta axis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-04T17%3A12%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_webof&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=CMTM6%20drives%20cisplatin%20resistance%20by%20regulating%20Wnt%20signaling%20through%20the%20ENO-1/AKT/GSK3%20beta%20axis&rft.jtitle=JCI%20insight&rft.au=Mohapatra,%20Pallavi&rft.date=2021-02-22&rft.volume=6&rft.issue=4&rft.artnum=143643&rft.issn=2379-3708&rft.eissn=2379-3708&rft_id=info:doi/10.1172/jci.insight.143643&rft_dat=%3Cproquest_webof%3E2477499373%3C/proquest_webof%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2477499373&rft_id=info:pmid/33434185&rft_doaj_id=oai_doaj_org_article_ff7cbbff47654536897a562f50eb8bc2&rfr_iscdi=true |