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Gemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy

2013-09Journal article Open access
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dc.contributor.authorHill, Richard
dc.contributor.authorRabb, M.
dc.contributor.authorA Madureira, Patricia
dc.contributor.authorClements, D.
dc.contributor.authorGujar, S. A.
dc.contributor.authorWaisman, D. M.
dc.contributor.authorGiacomantonio, C. A.
dc.contributor.authorLee, P. W. K.
dc.date.accessioned2018-12-07T14:58:12Z
dc.date.available2018-12-07T14:58:12Z
dc.date.issued2013-09
dc.description.abstractGemcitabine is a chemotherapeutic that is widely used for the treatment of a variety of haematological malignancies and has become the standard chemotherapy for the treatment of advanced pancreatic cancer. Combinational gemcitabine regimes (e.g. with doxorubicin) are being tested in clinical trials to treat a variety of cancers, including colon cancer. The limited success of these trials has prompted us to pursue a better understanding of gemcitabine's mechanism of cell killing, which could dramatically improve the therapeutic potential of this agent. For comparison, we included gamma irradiation that triggers robust cell cycle arrest and Cr(VI), which is a highly toxic chemical that induces a robust p53-dependent apoptotic response. Gemcitabine induced a potent p53-dependent apoptosis that correlated with the accumulation of pro-apoptotic proteins such as PUMA and Bax. This is accompanied by a drastic reduction in p2l and 14-3-3 sigma protein levels, thereby significantly sensitizing the cells to apoptosis. In vitro and in vivo studies demonstrated that gemcitabine required PUMA transcription to instigate an apoptotic programme. This was in contrast to Cr(VI)-induced apoptosis that required Bax and was independent of transcription. An examination of clinical colon and pancreatic cancer tissues shows higher p53, p21, 14-3-3 sigma and Bax expression compared with matched normal tissues, yet there is a near absence of PUMA protein. This may explain why gemcitabine shows only limited efficacy in the treatment of these cancers. Our results raise the possibility that targeting the Bax-dependent cell death pathway, rather than the PUMA pathway, could result in significantly improved patient outcome and prognosis for these cancers.
dc.description.sponsorshipFundacao para a Ciencia e a Tecnologia (FCT) [SFRH/BPD/84634/2012]; European Union [PCOFUND-GA-2009-246542]; Foundation for Science and Technology of Portugal; Canadian Institute of Health Research
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1038/cddis.2013.307
dc.identifier.issn2041-4889
dc.identifier.urihttp://hdl.handle.net/10400.1/11913
dc.language.isoeng
dc.peerreviewedyes
dc.publisherNature Publishing Group
dc.relationWORK PLAN FOR RESEARCH FELLOWSHIP PCOFUND-GA-2009-246542
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectErlotinib plus gemcitabine
dc.subjectP53 target genes
dc.subjectDna-damage
dc.subjectMutational analysis
dc.subjectCellular-response
dc.subjectBinding-sites
dc.subjectApoptosis
dc.subjectChromium
dc.subjectCells
dc.subjectActivation
dc.titleGemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleWORK PLAN FOR RESEARCH FELLOWSHIP PCOFUND-GA-2009-246542
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F84634%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBI%2F52182%2F2013/PT
oaire.citation.startPagee791
oaire.citation.titleCell Death and Disease
oaire.citation.volume4
oaire.fundingStreamSFRH
person.familyNameHill
person.familyNameMadureira
person.givenNameRichard
person.givenNamePatricia
person.identifier.ciencia-id6612-9A86-6929
person.identifier.orcid0000-0003-0394-6048
person.identifier.orcid0000-0002-4856-3908
person.identifier.scopus-author-id55266604200
person.identifier.scopus-author-id10340140500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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relation.isAuthorOfPublicationa40de6a3-d52d-45dd-8620-cb94a22ebc8f
relation.isAuthorOfPublication.latestForDiscoverye67f4a4f-aa35-4740-87b0-0cd07a9e1993
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