Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells
Abstract PEL cells relay on the constitutive activation of STAT3 for their survival, thus its inhibition by AG490 leads to apoptotic cell death. In this study, we found that the cytotoxic activity of AG490 correlated with the reduction of HSP70 and its master regulator HSF1 that, based on knocking-d...
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| Veröffentlicht in: | Cancer letters 2015-10, Vol.366 (2), p.191-197 |
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| container_title | Cancer letters |
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| creator | Granato, Marisa Chiozzi, Barbara Filardi, Maria Rosaria Lotti, Lavinia Vittoria Di Renzo, Livia Faggioni, Alberto Cirone, Mara |
| description | Abstract PEL cells relay on the constitutive activation of STAT3 for their survival, thus its inhibition by AG490 leads to apoptotic cell death. In this study, we found that the cytotoxic activity of AG490 correlated with the reduction of HSP70 and its master regulator HSF1 that, based on knocking-down experiments, was found to play a pro-survival role in PEL cells. To counteract the pro-death effect mediated by HSF1/HSP70 down-regulation, AG490 induced a complete autophagy, whose inhibition potentiated its cytotoxic effect against PEL cells. AG490 as well as HSF1 siRNA reduced the expression of Mcl-1, a Bcl-2 family member that negatively regulates apoptosis and autophagy. These results suggest that STAT3 inhibition, by down-regulating the expression of HSF1/HSP70, reduces Mcl-1 and leads to both apoptosis and autophagy induction in PEL cells. |
| doi_str_mv | 10.1016/j.canlet.2015.07.006 |
| format | Article |
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In this study, we found that the cytotoxic activity of AG490 correlated with the reduction of HSP70 and its master regulator HSF1 that, based on knocking-down experiments, was found to play a pro-survival role in PEL cells. To counteract the pro-death effect mediated by HSF1/HSP70 down-regulation, AG490 induced a complete autophagy, whose inhibition potentiated its cytotoxic effect against PEL cells. AG490 as well as HSF1 siRNA reduced the expression of Mcl-1, a Bcl-2 family member that negatively regulates apoptosis and autophagy. These results suggest that STAT3 inhibition, by down-regulating the expression of HSF1/HSP70, reduces Mcl-1 and leads to both apoptosis and autophagy induction in PEL cells.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2015.07.006</identifier><identifier>PMID: 26184999</identifier><language>eng</language><publisher>Ireland: Elsevier Ireland Ltd</publisher><subject>AG490 ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Autophagy ; Biotechnology ; Cancer ; Cell Line, Tumor ; Cytotoxicity ; DNA-Binding Proteins - drug effects ; Dose-Response Relationship, Drug ; Down-Regulation ; Enzyme Inhibitors - pharmacology ; Heat Shock Transcription Factors ; Hematology, Oncology and Palliative Medicine ; HSF1 ; Humans ; Immunoglobulins ; Kinases ; Laboratories ; Lymphoma ; Lymphoma, B-Cell - drug therapy ; Lymphoma, B-Cell - immunology ; Lymphoma, B-Cell - metabolism ; Lymphoma, B-Cell - pathology ; Mcl-1 ; Myeloid Cell Leukemia Sequence 1 Protein - drug effects ; PEL ; Phosphorylation ; Protein folding ; Protein-Tyrosine Kinases - antagonists & inhibitors ; STAT3 ; STAT3 Transcription Factor - drug effects ; Studies ; Transcription factors ; Transcription Factors - drug effects ; Tumor Cells, Cultured ; Tyrphostins - pharmacology</subject><ispartof>Cancer letters, 2015-10, Vol.366 (2), p.191-197</ispartof><rights>Elsevier Ireland Ltd</rights><rights>2015 Elsevier Ireland Ltd</rights><rights>Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited Oct 1, 2015</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c515t-b99242be444a4551731438e431f0d726bfa7ed35ba21db54fc06ad94819a49e73</citedby><cites>FETCH-LOGICAL-c515t-b99242be444a4551731438e431f0d726bfa7ed35ba21db54fc06ad94819a49e73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.canlet.2015.07.006$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26184999$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Granato, Marisa</creatorcontrib><creatorcontrib>Chiozzi, Barbara</creatorcontrib><creatorcontrib>Filardi, Maria Rosaria</creatorcontrib><creatorcontrib>Lotti, Lavinia Vittoria</creatorcontrib><creatorcontrib>Di Renzo, Livia</creatorcontrib><creatorcontrib>Faggioni, Alberto</creatorcontrib><creatorcontrib>Cirone, Mara</creatorcontrib><title>Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>Abstract PEL cells relay on the constitutive activation of STAT3 for their survival, thus its inhibition by AG490 leads to apoptotic cell death. In this study, we found that the cytotoxic activity of AG490 correlated with the reduction of HSP70 and its master regulator HSF1 that, based on knocking-down experiments, was found to play a pro-survival role in PEL cells. To counteract the pro-death effect mediated by HSF1/HSP70 down-regulation, AG490 induced a complete autophagy, whose inhibition potentiated its cytotoxic effect against PEL cells. AG490 as well as HSF1 siRNA reduced the expression of Mcl-1, a Bcl-2 family member that negatively regulates apoptosis and autophagy. These results suggest that STAT3 inhibition, by down-regulating the expression of HSF1/HSP70, reduces Mcl-1 and leads to both apoptosis and autophagy induction in PEL cells.</description><subject>AG490</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Cytotoxicity</subject><subject>DNA-Binding Proteins - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Down-Regulation</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Heat Shock Transcription Factors</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>HSF1</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Lymphoma</subject><subject>Lymphoma, B-Cell - drug therapy</subject><subject>Lymphoma, B-Cell - immunology</subject><subject>Lymphoma, B-Cell - metabolism</subject><subject>Lymphoma, B-Cell - pathology</subject><subject>Mcl-1</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - drug effects</subject><subject>PEL</subject><subject>Phosphorylation</subject><subject>Protein folding</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>STAT3</subject><subject>STAT3 Transcription Factor - drug effects</subject><subject>Studies</subject><subject>Transcription factors</subject><subject>Transcription Factors - drug effects</subject><subject>Tumor Cells, Cultured</subject><subject>Tyrphostins - pharmacology</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkktv1DAUhS0EosPAP0DIEhs2CdeJndgbpKrqA2kQSC1ry3HuzHiacYLtVOTfkzAFpG5YeeHvnPs4l5C3DHIGrPp4yK3xHaa8ACZyqHOA6hlZMVkXWa0kPCcrKIFnpSzFGXkV4wEABK_FS3JWVExypdSK_LybQh-dR3rvvIlInd-7xqU-0DSFYd_H5Dw9v-YKaAput8MQadOnPTVDP6RZGqnxLTVj6oe92U20mWjAdrTO7-jN7RX7_f3Fdhmbvem3yw212HXxNXmxNV3EN4_vmny_ury7uMk2X68_X5xvMiuYSFmjVMGLBjnnhgvB6pLxUiIv2RbauqiaramxLUVjCtY2gm8tVKZVXDJluMK6XJMPJ98h9D9GjEkfXVw6MB77MWpWAzAolJQz-v4JeujH4OfuFkoyLtRcfE34ibLz4mLArR6CO5owaQZ6SUYf9CkZvSSjodZzMrPs3aP52Byx_Sv6E8UMfDoBOG_jwWHQ0Tr0FlsX0Cbd9u5_FZ4a2M55Z013jxPGf7PoWGjQt8t1LMfBBADnsip_AbS5tFk</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Granato, Marisa</creator><creator>Chiozzi, Barbara</creator><creator>Filardi, Maria Rosaria</creator><creator>Lotti, Lavinia Vittoria</creator><creator>Di Renzo, Livia</creator><creator>Faggioni, Alberto</creator><creator>Cirone, Mara</creator><general>Elsevier Ireland Ltd</general><general>Elsevier Limited</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>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20151001</creationdate><title>Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells</title><author>Granato, Marisa ; Chiozzi, Barbara ; Filardi, Maria Rosaria ; Lotti, Lavinia Vittoria ; Di Renzo, Livia ; Faggioni, Alberto ; Cirone, Mara</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c515t-b99242be444a4551731438e431f0d726bfa7ed35ba21db54fc06ad94819a49e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>AG490</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Autophagy</topic><topic>Biotechnology</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Cytotoxicity</topic><topic>DNA-Binding Proteins - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Down-Regulation</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Heat Shock Transcription Factors</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>HSF1</topic><topic>Humans</topic><topic>Immunoglobulins</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Lymphoma</topic><topic>Lymphoma, B-Cell - drug therapy</topic><topic>Lymphoma, B-Cell - immunology</topic><topic>Lymphoma, B-Cell - metabolism</topic><topic>Lymphoma, B-Cell - pathology</topic><topic>Mcl-1</topic><topic>Myeloid Cell Leukemia Sequence 1 Protein - drug effects</topic><topic>PEL</topic><topic>Phosphorylation</topic><topic>Protein folding</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>STAT3</topic><topic>STAT3 Transcription Factor - drug effects</topic><topic>Studies</topic><topic>Transcription factors</topic><topic>Transcription Factors - drug effects</topic><topic>Tumor Cells, Cultured</topic><topic>Tyrphostins - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Granato, Marisa</creatorcontrib><creatorcontrib>Chiozzi, Barbara</creatorcontrib><creatorcontrib>Filardi, Maria Rosaria</creatorcontrib><creatorcontrib>Lotti, Lavinia Vittoria</creatorcontrib><creatorcontrib>Di Renzo, Livia</creatorcontrib><creatorcontrib>Faggioni, Alberto</creatorcontrib><creatorcontrib>Cirone, Mara</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Granato, Marisa</au><au>Chiozzi, Barbara</au><au>Filardi, Maria Rosaria</au><au>Lotti, Lavinia Vittoria</au><au>Di Renzo, Livia</au><au>Faggioni, Alberto</au><au>Cirone, Mara</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>366</volume><issue>2</issue><spage>191</spage><epage>197</epage><pages>191-197</pages><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>Abstract PEL cells relay on the constitutive activation of STAT3 for their survival, thus its inhibition by AG490 leads to apoptotic cell death. In this study, we found that the cytotoxic activity of AG490 correlated with the reduction of HSP70 and its master regulator HSF1 that, based on knocking-down experiments, was found to play a pro-survival role in PEL cells. To counteract the pro-death effect mediated by HSF1/HSP70 down-regulation, AG490 induced a complete autophagy, whose inhibition potentiated its cytotoxic effect against PEL cells. AG490 as well as HSF1 siRNA reduced the expression of Mcl-1, a Bcl-2 family member that negatively regulates apoptosis and autophagy. These results suggest that STAT3 inhibition, by down-regulating the expression of HSF1/HSP70, reduces Mcl-1 and leads to both apoptosis and autophagy induction in PEL cells.</abstract><cop>Ireland</cop><pub>Elsevier Ireland Ltd</pub><pmid>26184999</pmid><doi>10.1016/j.canlet.2015.07.006</doi><tpages>7</tpages></addata></record> |
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| subjects | AG490 Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Autophagy Biotechnology Cancer Cell Line, Tumor Cytotoxicity DNA-Binding Proteins - drug effects Dose-Response Relationship, Drug Down-Regulation Enzyme Inhibitors - pharmacology Heat Shock Transcription Factors Hematology, Oncology and Palliative Medicine HSF1 Humans Immunoglobulins Kinases Laboratories Lymphoma Lymphoma, B-Cell - drug therapy Lymphoma, B-Cell - immunology Lymphoma, B-Cell - metabolism Lymphoma, B-Cell - pathology Mcl-1 Myeloid Cell Leukemia Sequence 1 Protein - drug effects PEL Phosphorylation Protein folding Protein-Tyrosine Kinases - antagonists & inhibitors STAT3 STAT3 Transcription Factor - drug effects Studies Transcription factors Transcription Factors - drug effects Tumor Cells, Cultured Tyrphostins - pharmacology |
| title | Tyrosine kinase inhibitor tyrphostin AG490 triggers both apoptosis and autophagy by reducing HSF1 and Mcl-1 in PEL cells |
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