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Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy
Our previous studies indicate that phosphatidylinositol 4-kinase IIα can promote the growth of multi-malignant tumors viaHER-2/PI3K andMAPK pathways.However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KIIα could...
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| Published in: | Protein & cell 2014-06, Vol.5 (6), p.457-468 |
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| container_end_page | 468 |
| container_issue | 6 |
| container_start_page | 457 |
| container_title | Protein & cell |
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| creator | Li, Jiangmei Zhang, Lunfeng Gao, Zhen Kang, Hua Rong, Guohua Zhang, Xu Chen, Chang |
| description | Our previous studies indicate that phosphatidylinositol 4-kinase IIα can promote the growth of multi-malignant tumors viaHER-2/PI3K andMAPK pathways.However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KIIα could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KIIα knockdown reduced EGFR protein level, and the expression ofPI4KIIα shows a strong correlation with EGFR in human breast cancer tissues ( r = 0.77, P |
| doi_str_mv | 10.1007/s13238-014-0055-y |
| format | article |
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In this study, we found that PI4KIIα could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KIIα knockdown reduced EGFR protein level, and the expression ofPI4KIIα shows a strong correlation with EGFR in human breast cancer tissues ( r = 0.77, P<0.01). PI4KIIα knockdown greatly prolonged the effects and decreased the effective dosage ofAG-1478, a specific inhibitor of EGFR. In addition, it significantly enhanced AG1478-induced inhibition of tumor cell survival and strengthened the effect of the EGFR-targeting anti-cancer drug Iressa in xenograft tumor models. Mechanistically, we found that PI4KIIα suppression increased EGFR ligand-independent degradation. Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture (SILAC) and LC-MS/MS suggested that HSP90mediated the effect of PI4KIIα onEGFR. Furthermore, we found that combined inhibition of PI4KIIα and EGFR suppressed both PI3K/AKT and MAPK/ERK pathways, and resulted in downregulation of multiple oncogenes like PRDX2, FASN, MTA2, ultimately leading to suppression of tumor growth. Therefore,we conclude that combined inhibition of PI4KIIα and EGFR exerts a multiple anti-tumor effect. Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα presents anovel strategy tocombatEGFR-dependent tumors.</description><identifier>ISSN: 1674-800X</identifier><identifier>EISSN: 1674-8018</identifier><identifier>DOI: 10.1007/s13238-014-0055-y</identifier><identifier>PMID: 24801752</identifier><language>eng</language><publisher>Beijing: Higher Education Press</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Biochemistry ; Biomedical and Life Sciences ; breast cancer ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Biology ; Cell Line, Tumor ; Cell Survival - drug effects ; Developmental Biology ; dual inhibition ; EGFR ; enhanced anti-tumor effect ; Female ; HSP90 Heat-Shock Proteins - metabolism ; Human Genetics ; Humans ; Iressa ; Life Sciences ; Male ; MCF-7 Cells ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Minor Histocompatibility Antigens ; Mitogen-Activated Protein Kinases - metabolism ; Phosphatidylinositol 3-Kinases - metabolism ; phosphatidylinositol 4-kinase IIα (PI4KIIα) ; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors ; Phosphotransferases (Alcohol Group Acceptor) - genetics ; Phosphotransferases (Alcohol Group Acceptor) - metabolism ; Protein Science ; Proto-Oncogene Proteins c-akt - metabolism ; Quinazolines - pharmacology ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - metabolism ; Research Article ; Stem Cells ; Transplantation, Heterologous ; Tyrphostins - pharmacology</subject><ispartof>Protein & cell, 2014-06, Vol.5 (6), p.457-468</ispartof><rights>Copyright reserved, 2014, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>The Author(s) 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-5adfad409cfd0876643116df80df43a403aa3ed9e5cb9e00b08132c8d1c9ba253</citedby><cites>FETCH-LOGICAL-c491t-5adfad409cfd0876643116df80df43a403aa3ed9e5cb9e00b08132c8d1c9ba253</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/PMC4026421/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026421/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,37013,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24801752$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Jiangmei</creatorcontrib><creatorcontrib>Zhang, Lunfeng</creatorcontrib><creatorcontrib>Gao, Zhen</creatorcontrib><creatorcontrib>Kang, Hua</creatorcontrib><creatorcontrib>Rong, Guohua</creatorcontrib><creatorcontrib>Zhang, Xu</creatorcontrib><creatorcontrib>Chen, Chang</creatorcontrib><title>Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy</title><title>Protein & cell</title><addtitle>Protein Cell</addtitle><addtitle>Protein Cell</addtitle><description>Our previous studies indicate that phosphatidylinositol 4-kinase IIα can promote the growth of multi-malignant tumors viaHER-2/PI3K andMAPK pathways.However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KIIα could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KIIα knockdown reduced EGFR protein level, and the expression ofPI4KIIα shows a strong correlation with EGFR in human breast cancer tissues ( r = 0.77, P<0.01). PI4KIIα knockdown greatly prolonged the effects and decreased the effective dosage ofAG-1478, a specific inhibitor of EGFR. In addition, it significantly enhanced AG1478-induced inhibition of tumor cell survival and strengthened the effect of the EGFR-targeting anti-cancer drug Iressa in xenograft tumor models. Mechanistically, we found that PI4KIIα suppression increased EGFR ligand-independent degradation. Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture (SILAC) and LC-MS/MS suggested that HSP90mediated the effect of PI4KIIα onEGFR. Furthermore, we found that combined inhibition of PI4KIIα and EGFR suppressed both PI3K/AKT and MAPK/ERK pathways, and resulted in downregulation of multiple oncogenes like PRDX2, FASN, MTA2, ultimately leading to suppression of tumor growth. Therefore,we conclude that combined inhibition of PI4KIIα and EGFR exerts a multiple anti-tumor effect. Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα presents anovel strategy tocombatEGFR-dependent tumors.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>breast cancer</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Developmental Biology</subject><subject>dual inhibition</subject><subject>EGFR</subject><subject>enhanced anti-tumor effect</subject><subject>Female</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Iressa</subject><subject>Life Sciences</subject><subject>Male</subject><subject>MCF-7 Cells</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Minor Histocompatibility Antigens</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>phosphatidylinositol 4-kinase IIα (PI4KIIα)</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - genetics</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - metabolism</subject><subject>Protein Science</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Quinazolines - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>Research Article</subject><subject>Stem Cells</subject><subject>Transplantation, Heterologous</subject><subject>Tyrphostins - pharmacology</subject><issn>1674-800X</issn><issn>1674-8018</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNp9kc9u1DAQxiMEolXpA3BBPnJJGcfOvwsSKm1ZtRIIgcTNcuxJ1iWxF9tZKY_Fi_BMeJV2BZf6Mpbm-34zmi_LXlO4oAD1u0BZwZocKM8ByjJfnmWntKp53gBtnh__8OMkOw_hHtJjjJZV_TI7KXgS1WVxmoWPsxyJsVvTmWicJa4nVzfXX4mMZOddRGOJtJpIFc3exIWMuMeR7I0kyk2dsTI6bxKiG536aexwAHzZ8NvN5s9vIkMyR5PHeXKehOhlxGF5lb3o5Rjw_KGeZd-vr75dfsrvPt9sLj_c5Yq3NOal1L3UHFrVa2jqquKM0kr3DeieM8mBSclQt1iqrkWADpp0EtVoqtpOFiU7y96v3N3cTagV2rTAKHbeTNIvwkkj_u9YsxWD2wsORcULmgBvHwDe_ZoxRDGZoHAcpUU3B0HLoqpZVTFIUrpKlXcheOyPYyiIQ15izUukvMQhL7Ekz5t_9zs6HtNJgmIVhNSyA3px72Zv082epDaraWuGLXrUO48hiN67lAT6p6x_AdhQthM</recordid><startdate>20140601</startdate><enddate>20140601</enddate><creator>Li, Jiangmei</creator><creator>Zhang, Lunfeng</creator><creator>Gao, Zhen</creator><creator>Kang, Hua</creator><creator>Rong, Guohua</creator><creator>Zhang, Xu</creator><creator>Chen, Chang</creator><general>Higher Education Press</general><scope>C6C</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></search><sort><creationdate>20140601</creationdate><title>Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy</title><author>Li, Jiangmei ; Zhang, Lunfeng ; Gao, Zhen ; Kang, Hua ; Rong, Guohua ; Zhang, Xu ; Chen, Chang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-5adfad409cfd0876643116df80df43a403aa3ed9e5cb9e00b08132c8d1c9ba253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>breast cancer</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Developmental Biology</topic><topic>dual inhibition</topic><topic>EGFR</topic><topic>enhanced anti-tumor effect</topic><topic>Female</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Iressa</topic><topic>Life Sciences</topic><topic>Male</topic><topic>MCF-7 Cells</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Minor Histocompatibility Antigens</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>phosphatidylinositol 4-kinase IIα (PI4KIIα)</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - genetics</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - metabolism</topic><topic>Protein Science</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Quinazolines - pharmacology</topic><topic>Receptor, Epidermal Growth Factor - antagonists & inhibitors</topic><topic>Receptor, Epidermal Growth Factor - metabolism</topic><topic>Research Article</topic><topic>Stem Cells</topic><topic>Transplantation, Heterologous</topic><topic>Tyrphostins - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Jiangmei</creatorcontrib><creatorcontrib>Zhang, Lunfeng</creatorcontrib><creatorcontrib>Gao, Zhen</creatorcontrib><creatorcontrib>Kang, Hua</creatorcontrib><creatorcontrib>Rong, Guohua</creatorcontrib><creatorcontrib>Zhang, Xu</creatorcontrib><creatorcontrib>Chen, Chang</creatorcontrib><collection>SpringerOpen</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><jtitle>Protein & cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Jiangmei</au><au>Zhang, Lunfeng</au><au>Gao, Zhen</au><au>Kang, Hua</au><au>Rong, Guohua</au><au>Zhang, Xu</au><au>Chen, Chang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy</atitle><jtitle>Protein & cell</jtitle><stitle>Protein Cell</stitle><addtitle>Protein Cell</addtitle><date>2014-06-01</date><risdate>2014</risdate><volume>5</volume><issue>6</issue><spage>457</spage><epage>468</epage><pages>457-468</pages><issn>1674-800X</issn><eissn>1674-8018</eissn><abstract>Our previous studies indicate that phosphatidylinositol 4-kinase IIα can promote the growth of multi-malignant tumors viaHER-2/PI3K andMAPK pathways.However, the molecular mechanisms of this pathway and its potential for clinical application remain unknown. In this study, we found that PI4KIIα could be an ideal combinatorial target for EGFR treatment via regulating EGFR degradation. Results showed that PI4KIIα knockdown reduced EGFR protein level, and the expression ofPI4KIIα shows a strong correlation with EGFR in human breast cancer tissues ( r = 0.77, P<0.01). PI4KIIα knockdown greatly prolonged the effects and decreased the effective dosage ofAG-1478, a specific inhibitor of EGFR. In addition, it significantly enhanced AG1478-induced inhibition of tumor cell survival and strengthened the effect of the EGFR-targeting anti-cancer drug Iressa in xenograft tumor models. Mechanistically, we found that PI4KIIα suppression increased EGFR ligand-independent degradation. Quantitative proteomic analysis by stable isotope labeling with amino acids in cell culture (SILAC) and LC-MS/MS suggested that HSP90mediated the effect of PI4KIIα onEGFR. Furthermore, we found that combined inhibition of PI4KIIα and EGFR suppressed both PI3K/AKT and MAPK/ERK pathways, and resulted in downregulation of multiple oncogenes like PRDX2, FASN, MTA2, ultimately leading to suppression of tumor growth. Therefore,we conclude that combined inhibition of PI4KIIα and EGFR exerts a multiple anti-tumor effect. Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα presents anovel strategy tocombatEGFR-dependent tumors.</abstract><cop>Beijing</cop><pub>Higher Education Press</pub><pmid>24801752</pmid><doi>10.1007/s13238-014-0055-y</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Protein & cell, 2014-06, Vol.5 (6), p.457-468 |
| issn | 1674-800X 1674-8018 |
| language | eng |
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| source | Open Access: Oxford University Press Open Journals; Springer Nature - SpringerLink Journals - Fully Open Access ; Publicly Available Content (ProQuest); PubMed Central |
| subjects | Animals Antineoplastic Agents - pharmacology Biochemistry Biomedical and Life Sciences breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Biology Cell Line, Tumor Cell Survival - drug effects Developmental Biology dual inhibition EGFR enhanced anti-tumor effect Female HSP90 Heat-Shock Proteins - metabolism Human Genetics Humans Iressa Life Sciences Male MCF-7 Cells Mice Mice, Inbred BALB C Mice, Nude Minor Histocompatibility Antigens Mitogen-Activated Protein Kinases - metabolism Phosphatidylinositol 3-Kinases - metabolism phosphatidylinositol 4-kinase IIα (PI4KIIα) Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors Phosphotransferases (Alcohol Group Acceptor) - genetics Phosphotransferases (Alcohol Group Acceptor) - metabolism Protein Science Proto-Oncogene Proteins c-akt - metabolism Quinazolines - pharmacology Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - metabolism Research Article Stem Cells Transplantation, Heterologous Tyrphostins - pharmacology |
| title | Dual inhibition of EGFR at protein and activity level via combinatorial blocking of PI4KIIα as anti-tumor strategy |
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