Loading…

Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3

The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activ...

Full description

Saved in:
Bibliographic Details
Published in:Neoplasia (New York, N.Y.) N.Y.), 2010-07, Vol.12 (7), p.527-538
Main Authors: St Germain, Carly, Niknejad, Nima, Ma, Laurie, Garbuio, Kyla, Hai, Tsonwin, Dimitroulakos, Jim
Format: Article
Language:English
Subjects:
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites
container_end_page 538
container_issue 7
container_start_page 527
container_title Neoplasia (New York, N.Y.)
container_volume 12
creator St Germain, Carly
Niknejad, Nima
Ma, Laurie
Garbuio, Kyla
Hai, Tsonwin
Dimitroulakos, Jim
description The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.
doi_str_mv 10.1593/neo.92048
format article
fullrecord <record><control><sourceid>pubmed</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2907579</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>20651982</sourcerecordid><originalsourceid>FETCH-LOGICAL-p265t-e5e3d2639237d7f7054acb138d0413ee1f987a0b67f1bac9e67d45805b8123a53</originalsourceid><addsrcrecordid>eNpVkMtKxDAYhYMozji68AUkL9Axl-a2EWTwBoIbXZc0SdvoTFKazGh9eguOoqvzw_nPx-EAcI7REjNFL4OLS0VQKQ_AHJeCF4xJfjjdjJBCIkRm4CSlV4Qwx0IcgxlBnGElyRx8rnzq1zr7AH2wW-MSNGOOOX544_MIczfEbdtN6uDG59i6UGiT_U5nZ2E_xOym6JsPOjnY69y96zFBHSzcf_nQwjzokMzg--xjgM3kxAHSU3DU6HVyZ3tdgJfbm-fVffH4dPewun4sesJZLhxz1BJOFaHCikYgVmpTYyotKjF1DjdKCo1qLhpca6McF7ZkErFaYkI1owtw9c3tt_XGWePC1Gdd9YPf6GGsovbVfyf4rmrjriIKCSbUBLj4C_hN_qxIvwAtO3hf</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3</title><source>PubMed (Medline)</source><source>ScienceDirect Journals</source><creator>St Germain, Carly ; Niknejad, Nima ; Ma, Laurie ; Garbuio, Kyla ; Hai, Tsonwin ; Dimitroulakos, Jim</creator><creatorcontrib>St Germain, Carly ; Niknejad, Nima ; Ma, Laurie ; Garbuio, Kyla ; Hai, Tsonwin ; Dimitroulakos, Jim</creatorcontrib><description>The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.</description><identifier>ISSN: 1522-8002</identifier><identifier>EISSN: 1476-5586</identifier><identifier>DOI: 10.1593/neo.92048</identifier><identifier>PMID: 20651982</identifier><language>eng</language><publisher>United States: Neoplasia Press Inc</publisher><subject>Activating Transcription Factor 3 - genetics ; Activating Transcription Factor 3 - metabolism ; Activating Transcription Factor 3 - physiology ; Animals ; Cell Proliferation - drug effects ; Cells, Cultured ; Cisplatin - pharmacology ; Cytotoxins - pharmacology ; Female ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Expression Regulation, Neoplastic - physiology ; Genes, BRCA1 - physiology ; Genes, p53 - physiology ; Humans ; Male ; MAP Kinase Signaling System - drug effects ; MAP Kinase Signaling System - physiology ; Mice ; Mice, Transgenic ; Signal Transduction - drug effects ; Signal Transduction - genetics ; Signal Transduction - physiology</subject><ispartof>Neoplasia (New York, N.Y.), 2010-07, Vol.12 (7), p.527-538</ispartof><rights>Copyright © 2010 Neoplasia Press, Inc. All rights reserved</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907579/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907579/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20651982$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>St Germain, Carly</creatorcontrib><creatorcontrib>Niknejad, Nima</creatorcontrib><creatorcontrib>Ma, Laurie</creatorcontrib><creatorcontrib>Garbuio, Kyla</creatorcontrib><creatorcontrib>Hai, Tsonwin</creatorcontrib><creatorcontrib>Dimitroulakos, Jim</creatorcontrib><title>Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3</title><title>Neoplasia (New York, N.Y.)</title><addtitle>Neoplasia</addtitle><description>The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.</description><subject>Activating Transcription Factor 3 - genetics</subject><subject>Activating Transcription Factor 3 - metabolism</subject><subject>Activating Transcription Factor 3 - physiology</subject><subject>Animals</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Cisplatin - pharmacology</subject><subject>Cytotoxins - pharmacology</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Expression Regulation, Neoplastic - physiology</subject><subject>Genes, BRCA1 - physiology</subject><subject>Genes, p53 - physiology</subject><subject>Humans</subject><subject>Male</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>MAP Kinase Signaling System - physiology</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - genetics</subject><subject>Signal Transduction - physiology</subject><issn>1522-8002</issn><issn>1476-5586</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><recordid>eNpVkMtKxDAYhYMozji68AUkL9Axl-a2EWTwBoIbXZc0SdvoTFKazGh9eguOoqvzw_nPx-EAcI7REjNFL4OLS0VQKQ_AHJeCF4xJfjjdjJBCIkRm4CSlV4Qwx0IcgxlBnGElyRx8rnzq1zr7AH2wW-MSNGOOOX544_MIczfEbdtN6uDG59i6UGiT_U5nZ2E_xOym6JsPOjnY69y96zFBHSzcf_nQwjzokMzg--xjgM3kxAHSU3DU6HVyZ3tdgJfbm-fVffH4dPewun4sesJZLhxz1BJOFaHCikYgVmpTYyotKjF1DjdKCo1qLhpca6McF7ZkErFaYkI1owtw9c3tt_XGWePC1Gdd9YPf6GGsovbVfyf4rmrjriIKCSbUBLj4C_hN_qxIvwAtO3hf</recordid><startdate>20100701</startdate><enddate>20100701</enddate><creator>St Germain, Carly</creator><creator>Niknejad, Nima</creator><creator>Ma, Laurie</creator><creator>Garbuio, Kyla</creator><creator>Hai, Tsonwin</creator><creator>Dimitroulakos, Jim</creator><general>Neoplasia Press Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>5PM</scope></search><sort><creationdate>20100701</creationdate><title>Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3</title><author>St Germain, Carly ; Niknejad, Nima ; Ma, Laurie ; Garbuio, Kyla ; Hai, Tsonwin ; Dimitroulakos, Jim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p265t-e5e3d2639237d7f7054acb138d0413ee1f987a0b67f1bac9e67d45805b8123a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Activating Transcription Factor 3 - genetics</topic><topic>Activating Transcription Factor 3 - metabolism</topic><topic>Activating Transcription Factor 3 - physiology</topic><topic>Animals</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>Cisplatin - pharmacology</topic><topic>Cytotoxins - pharmacology</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene Expression Regulation, Neoplastic - physiology</topic><topic>Genes, BRCA1 - physiology</topic><topic>Genes, p53 - physiology</topic><topic>Humans</topic><topic>Male</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - genetics</topic><topic>Signal Transduction - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>St Germain, Carly</creatorcontrib><creatorcontrib>Niknejad, Nima</creatorcontrib><creatorcontrib>Ma, Laurie</creatorcontrib><creatorcontrib>Garbuio, Kyla</creatorcontrib><creatorcontrib>Hai, Tsonwin</creatorcontrib><creatorcontrib>Dimitroulakos, Jim</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neoplasia (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>St Germain, Carly</au><au>Niknejad, Nima</au><au>Ma, Laurie</au><au>Garbuio, Kyla</au><au>Hai, Tsonwin</au><au>Dimitroulakos, Jim</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3</atitle><jtitle>Neoplasia (New York, N.Y.)</jtitle><addtitle>Neoplasia</addtitle><date>2010-07-01</date><risdate>2010</risdate><volume>12</volume><issue>7</issue><spage>527</spage><epage>538</epage><pages>527-538</pages><issn>1522-8002</issn><eissn>1476-5586</eissn><abstract>The mechanisms underlying the proapoptotic effect of the chemotherapeutic agent, cisplatin, are largely undefined. Understanding the mechanisms regulating cisplatin cytotoxicity may uncover strategies to enhance the efficacy of this important therapeutic agent. This study evaluates the role of activating transcription factor 3 (ATF3) as a mediator of cisplatin-induced cytotoxicity. Cytotoxic doses of cisplatin and carboplatin treatments consistently induced ATF3 expression in five tumor-derived cell lines. Characterization of this induction revealed a p53, BRCA1, and integrated stress response-independent mechanism, all previously implicated in stress-mediated ATF3 induction. Analysis of mitogen-activated protein kinase (MAPK) pathway involvement in ATF3 induction by cisplatin revealed a MAPK-dependent mechanism. Cisplatin treatment combined with specific inhibitors to each MAPK pathway (c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38) resulted in decreased ATF3 induction at the protein level. MAPK pathway inhibition led to decreased ATF3 messenger RNA expression and reduced cytotoxic effects of cisplatin as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay. In A549 lung carcinoma cells, targeting ATF3 with specific small hairpin RNA also attenuated the cytotoxic effects of cisplatin. Similarly, ATF3-/- murine embryonic fibroblasts (MEFs) were shown to be less sensitive to cisplatin-induced cytotoxicity compared with ATF3+/+ MEFs. This study identifies cisplatin as a MAPK pathway-dependent inducer of ATF3, whose expression influences cisplatin's cytotoxic effects.</abstract><cop>United States</cop><pub>Neoplasia Press Inc</pub><pmid>20651982</pmid><doi>10.1593/neo.92048</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1522-8002
ispartof Neoplasia (New York, N.Y.), 2010-07, Vol.12 (7), p.527-538
issn 1522-8002
1476-5586
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2907579
source PubMed (Medline); ScienceDirect Journals
subjects Activating Transcription Factor 3 - genetics
Activating Transcription Factor 3 - metabolism
Activating Transcription Factor 3 - physiology
Animals
Cell Proliferation - drug effects
Cells, Cultured
Cisplatin - pharmacology
Cytotoxins - pharmacology
Female
Gene Expression Regulation, Neoplastic - drug effects
Gene Expression Regulation, Neoplastic - physiology
Genes, BRCA1 - physiology
Genes, p53 - physiology
Humans
Male
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Mice
Mice, Transgenic
Signal Transduction - drug effects
Signal Transduction - genetics
Signal Transduction - physiology
title Cisplatin induces cytotoxicity through the mitogen-activated protein kinase pathways and activating transcription factor 3
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-17T21%3A07%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cisplatin%20induces%20cytotoxicity%20through%20the%20mitogen-activated%20protein%20kinase%20pathways%20and%20activating%20transcription%20factor%203&rft.jtitle=Neoplasia%20(New%20York,%20N.Y.)&rft.au=St%20Germain,%20Carly&rft.date=2010-07-01&rft.volume=12&rft.issue=7&rft.spage=527&rft.epage=538&rft.pages=527-538&rft.issn=1522-8002&rft.eissn=1476-5586&rft_id=info:doi/10.1593/neo.92048&rft_dat=%3Cpubmed%3E20651982%3C/pubmed%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-p265t-e5e3d2639237d7f7054acb138d0413ee1f987a0b67f1bac9e67d45805b8123a53%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/20651982&rfr_iscdi=true