Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways
Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechani...
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| creator | Chen, Weibo Wu, Junhua Shi, Hua Wang, Zhongxia Zhang, Guang Cao, Yin Jiang, Chunping Ding, Yitao |
| description | Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture. |
| doi_str_mv | 10.1155/2014/764981 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4095710</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A427024397</galeid><sourcerecordid>A427024397</sourcerecordid><originalsourceid>FETCH-LOGICAL-c593t-c08ac941cb87ed4a37dd1b02397774e7655d5140b9ea45b7e1a11c143dcd730b3</originalsourceid><addsrcrecordid>eNqFks1vEzEQxVcIRKvSE2eQJS4IFOJZ2-vdC1IUtQ2oCETgbM16J1m3G29Yeyn973FICR-X-jKW_PObmaeXZU-BvwFQappzkFNdyKqEB9lxLkBOCpDw8HAX4ig7DeGKp1NCwavicXaUK660rKrj7MeCthidZctIXYeR2DxVNu_t2MVxIHbmse4osGU_4Iq8q9lnCi5E9JaY82wxtvrXn8BiO_TjumWLi_OpnXygOJ1dR4a-Ye_xOp8uI0bBPmFsb_A2PMkerbALdHpXT7Kv52df5ovJ5ceLd_PZ5cSqSsSJ5SXaSoKtS02NRKGbBmqei0prLUkXSjUKJK8rQqlqTYAAFqRobKMFr8VJ9navux3rDTWWfBywM9vBbXC4NT068--Ld61Z99-N5JXSwJPAyzuBof82Uohm44LdmeWpH4OBAkpIXqae96JKloVQoHeqL_5Dr_px8MmJRKm8FKUU8IdaY0fG-VWfRrQ7UTOTuea5TD4k6vWeskMfwkCrw3bAzS4lZpcSs09Jop__bciB_Z2JBLzaA63zDd64e9Se7WFKCK3wAMsqbZmLn8OIyu4</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1552838431</pqid></control><display><type>article</type><title>Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways</title><source>PubMed (Medline)</source><source>MEDLINE</source><source>Wiley Open Access</source><source>Alma/SFX Local Collection</source><source>PubMed Central Open Access</source><creator>Chen, Weibo ; Wu, Junhua ; Shi, Hua ; Wang, Zhongxia ; Zhang, Guang ; Cao, Yin ; Jiang, Chunping ; Ding, Yitao</creator><contributor>Zhou, Jian</contributor><creatorcontrib>Chen, Weibo ; Wu, Junhua ; Shi, Hua ; Wang, Zhongxia ; Zhang, Guang ; Cao, Yin ; Jiang, Chunping ; Ding, Yitao ; Zhou, Jian</creatorcontrib><description>Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture.</description><identifier>ISSN: 2314-6133</identifier><identifier>EISSN: 2314-6141</identifier><identifier>DOI: 10.1155/2014/764981</identifier><identifier>PMID: 25057499</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Puplishing Corporation</publisher><subject>Angiogenesis ; Apoptosis ; Carcinoma, Hepatocellular - metabolism ; Cell growth ; Cell Line, Tumor ; Cell Survival ; Coculture Techniques ; Culture Media - chemistry ; Drug resistance ; Drug Resistance, Neoplasm ; Enzyme-Linked Immunosorbent Assay ; Hepatic Stellate Cells - cytology ; Humans ; Janus Kinase 2 - metabolism ; Kinases ; Ligands ; Liver cancer ; Liver cells ; Liver Neoplasms - metabolism ; Medical prognosis ; Medical research ; Microscopy, Fluorescence ; Niacinamide - analogs & derivatives ; Niacinamide - chemistry ; Phenylurea Compounds - chemistry ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins c-met - metabolism ; Rodents ; Signal Transduction ; STAT3 Transcription Factor - metabolism ; Surgery</subject><ispartof>BioMed research international, 2014-01, Vol.2014 (2014), p.1-10</ispartof><rights>Copyright © 2014 Weibo Chen et al.</rights><rights>COPYRIGHT 2014 John Wiley & Sons, Inc.</rights><rights>Copyright © 2014 Weibo Chen et al. Weibo Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</rights><rights>Copyright © 2014 Weibo Chen et al. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c593t-c08ac941cb87ed4a37dd1b02397774e7655d5140b9ea45b7e1a11c143dcd730b3</citedby><cites>FETCH-LOGICAL-c593t-c08ac941cb87ed4a37dd1b02397774e7655d5140b9ea45b7e1a11c143dcd730b3</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/PMC4095710/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4095710/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25057499$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Zhou, Jian</contributor><creatorcontrib>Chen, Weibo</creatorcontrib><creatorcontrib>Wu, Junhua</creatorcontrib><creatorcontrib>Shi, Hua</creatorcontrib><creatorcontrib>Wang, Zhongxia</creatorcontrib><creatorcontrib>Zhang, Guang</creatorcontrib><creatorcontrib>Cao, Yin</creatorcontrib><creatorcontrib>Jiang, Chunping</creatorcontrib><creatorcontrib>Ding, Yitao</creatorcontrib><title>Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways</title><title>BioMed research international</title><addtitle>Biomed Res Int</addtitle><description>Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture.</description><subject>Angiogenesis</subject><subject>Apoptosis</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival</subject><subject>Coculture Techniques</subject><subject>Culture Media - chemistry</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Hepatic Stellate Cells - cytology</subject><subject>Humans</subject><subject>Janus Kinase 2 - metabolism</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Liver cancer</subject><subject>Liver cells</subject><subject>Liver Neoplasms - metabolism</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Microscopy, Fluorescence</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - chemistry</subject><subject>Phenylurea Compounds - chemistry</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins c-met - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Surgery</subject><issn>2314-6133</issn><issn>2314-6141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFks1vEzEQxVcIRKvSE2eQJS4IFOJZ2-vdC1IUtQ2oCETgbM16J1m3G29Yeyn973FICR-X-jKW_PObmaeXZU-BvwFQappzkFNdyKqEB9lxLkBOCpDw8HAX4ig7DeGKp1NCwavicXaUK660rKrj7MeCthidZctIXYeR2DxVNu_t2MVxIHbmse4osGU_4Iq8q9lnCi5E9JaY82wxtvrXn8BiO_TjumWLi_OpnXygOJ1dR4a-Ye_xOp8uI0bBPmFsb_A2PMkerbALdHpXT7Kv52df5ovJ5ceLd_PZ5cSqSsSJ5SXaSoKtS02NRKGbBmqei0prLUkXSjUKJK8rQqlqTYAAFqRobKMFr8VJ9navux3rDTWWfBywM9vBbXC4NT068--Ld61Z99-N5JXSwJPAyzuBof82Uohm44LdmeWpH4OBAkpIXqae96JKloVQoHeqL_5Dr_px8MmJRKm8FKUU8IdaY0fG-VWfRrQ7UTOTuea5TD4k6vWeskMfwkCrw3bAzS4lZpcSs09Jop__bciB_Z2JBLzaA63zDd64e9Se7WFKCK3wAMsqbZmLn8OIyu4</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Chen, Weibo</creator><creator>Wu, Junhua</creator><creator>Shi, Hua</creator><creator>Wang, Zhongxia</creator><creator>Zhang, Guang</creator><creator>Cao, Yin</creator><creator>Jiang, Chunping</creator><creator>Ding, Yitao</creator><general>Hindawi Puplishing Corporation</general><general>Hindawi Publishing Corporation</general><general>John Wiley & Sons, Inc</general><general>Hindawi Limited</general><scope>AACQA</scope><scope>ADJCN</scope><scope>AHFXO</scope><scope>RHU</scope><scope>RHW</scope><scope>RHX</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>3V.</scope><scope>7QL</scope><scope>7QO</scope><scope>7T7</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>CWDGH</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>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140101</creationdate><title>Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways</title><author>Chen, Weibo ; Wu, Junhua ; Shi, Hua ; Wang, Zhongxia ; Zhang, Guang ; Cao, Yin ; Jiang, Chunping ; Ding, Yitao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c593t-c08ac941cb87ed4a37dd1b02397774e7655d5140b9ea45b7e1a11c143dcd730b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Angiogenesis</topic><topic>Apoptosis</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival</topic><topic>Coculture Techniques</topic><topic>Culture Media - chemistry</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Hepatic Stellate Cells - cytology</topic><topic>Humans</topic><topic>Janus Kinase 2 - metabolism</topic><topic>Kinases</topic><topic>Ligands</topic><topic>Liver cancer</topic><topic>Liver cells</topic><topic>Liver Neoplasms - metabolism</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Microscopy, Fluorescence</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Niacinamide - chemistry</topic><topic>Phenylurea Compounds - chemistry</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Proto-Oncogene Proteins c-met - metabolism</topic><topic>Rodents</topic><topic>Signal Transduction</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Surgery</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Weibo</creatorcontrib><creatorcontrib>Wu, Junhua</creatorcontrib><creatorcontrib>Shi, Hua</creatorcontrib><creatorcontrib>Wang, Zhongxia</creatorcontrib><creatorcontrib>Zhang, Guang</creatorcontrib><creatorcontrib>Cao, Yin</creatorcontrib><creatorcontrib>Jiang, Chunping</creatorcontrib><creatorcontrib>Ding, Yitao</creatorcontrib><collection>بنك معلومات "معرفة" لدراسات العلوم العسكرية والأمنية - e-Marefa Military & Security Database</collection><collection>الدوريات العلمية والإحصائية - e-Marefa Academic and Statistical Periodicals</collection><collection>معرفة - المحتوى العربي الأكاديمي المتكامل - e-Marefa Academic Complete</collection><collection>Hindawi Publishing Complete</collection><collection>Hindawi Publishing Subscription Journals</collection><collection>Hindawi Publishing Open Access Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Middle East & Africa Database</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BioMed research international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Weibo</au><au>Wu, Junhua</au><au>Shi, Hua</au><au>Wang, Zhongxia</au><au>Zhang, Guang</au><au>Cao, Yin</au><au>Jiang, Chunping</au><au>Ding, Yitao</au><au>Zhou, Jian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways</atitle><jtitle>BioMed research international</jtitle><addtitle>Biomed Res Int</addtitle><date>2014-01-01</date><risdate>2014</risdate><volume>2014</volume><issue>2014</issue><spage>1</spage><epage>10</epage><pages>1-10</pages><issn>2314-6133</issn><eissn>2314-6141</eissn><abstract>Purpose. Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals. We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance. Experimental Design. The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells. The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy. The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting. Results. LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK. LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance. The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture. Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells. The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation. The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance. Conclusions. HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway. A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture.</abstract><cop>Cairo, Egypt</cop><pub>Hindawi Puplishing Corporation</pub><pmid>25057499</pmid><doi>10.1155/2014/764981</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Angiogenesis Apoptosis Carcinoma, Hepatocellular - metabolism Cell growth Cell Line, Tumor Cell Survival Coculture Techniques Culture Media - chemistry Drug resistance Drug Resistance, Neoplasm Enzyme-Linked Immunosorbent Assay Hepatic Stellate Cells - cytology Humans Janus Kinase 2 - metabolism Kinases Ligands Liver cancer Liver cells Liver Neoplasms - metabolism Medical prognosis Medical research Microscopy, Fluorescence Niacinamide - analogs & derivatives Niacinamide - chemistry Phenylurea Compounds - chemistry Proteins Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-met - metabolism Rodents Signal Transduction STAT3 Transcription Factor - metabolism Surgery |
| title | Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGF/c-Met/Akt and Jak2/Stat3 Pathways |
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