dc.contributor.author | Yeh, Wei-Lan | |
dc.contributor.author | Shioda, Keiko | |
dc.contributor.author | Coser, Kathryn R. | |
dc.contributor.author | Rivizzigno, Danielle | |
dc.contributor.author | McSweeney, Kristen R. | |
dc.contributor.author | Shioda, Toshihiro | |
dc.date.accessioned | 2013-10-17T18:08:51Z | |
dc.date.issued | 2013 | |
dc.identifier.citation | Yeh, Wei-Lan, Keiko Shioda, Kathryn R. Coser, Danielle Rivizzigno, Kristen R. McSweeney, and Toshi Shioda. 2013. Fulvestrant-induced cell death and proteasomal degradation of estrogen receptor α protein in MCF-7 cells require the CSK c-Src tyrosine kinase. PLoS ONE 8(4): e60889. | en_US |
dc.identifier.issn | 1932-6203 | en_US |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:11181000 | |
dc.description.abstract | Fulvestrant is a representative pure antiestrogen and a Selective Estrogen Receptor Down-regulator (SERD). In contrast to the Selective Estrogen Receptor Modulators (SERMs) such as 4-hydroxytamoxifen that bind to estrogen receptor α (ERα) as antagonists or partial agonists, fulvestrant causes proteasomal degradation of ERα protein, shutting down the estrogen signaling to induce proliferation arrest and apoptosis of estrogen-dependent breast cancer cells. We performed genome-wide RNAi knockdown screenings for protein kinases required for fulvestrant-induced apoptosis of the MCF-7 estrogen-dependent human breast caner cells and identified the c-Src tyrosine kinase (CSK), a negative regulator of the oncoprotein c-Src and related protein tyrosine kinases, as one of the necessary molecules. Whereas RNAi knockdown of CSK in MCF-7 cells by shRNA-expressing lentiviruses strongly suppressed fulvestrant-induced cell death, CSK knockdown did not affect cytocidal actions of 4-hydroxytamoxifen or paclitaxel, a chemotherapeutic agent. In the absence of CSK, fulvestrant-induced proteasomal degradation of ERα protein was suppressed in both MCF-7 and T47D estrogen-dependent breast cancer cells whereas the TP53-mutated T47D cells were resistant to the cytocidal action of fulvestrant in the presence or absence of CSK. MCF-7 cell sensitivities to fulvestrant-induced cell death or ERα protein degradation was not affected by small-molecular-weight inhibitors of the tyrosine kinase activity of c-Src, suggesting possible involvement of other signaling molecules in CSK-dependent MCF-7 cell death induced by fulvestrant. Our observations suggest the importance of CSK in the determination of cellular sensitivity to the cytocidal action of fulvestrant. | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | Public Library of Science | en_US |
dc.relation.isversionof | doi:10.1371/journal.pone.0060889 | en_US |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617152/pdf/ | en_US |
dash.license | LAA | |
dc.subject | Biology | en_US |
dc.subject | Molecular Cell Biology | en_US |
dc.subject | Signal Transduction | en_US |
dc.subject | Membrane Receptor Signaling | en_US |
dc.subject | Hormone Receptor Signaling | en_US |
dc.subject | Signaling Cascades | en_US |
dc.subject | Apoptotic Signaling Cascade | en_US |
dc.subject | Cell Death | en_US |
dc.subject | Medicine | en_US |
dc.subject | Obstetrics and Gynecology | en_US |
dc.subject | Breast Cancer | en_US |
dc.subject | Oncology | en_US |
dc.subject | Cancer Treatment | en_US |
dc.subject | Endocrine Therapy | en_US |
dc.title | Fulvestrant-Induced Cell Death and Proteasomal Degradation of Estrogen Receptor α Protein in MCF-7 Cells Require the CSK c-Src Tyrosine Kinase | en_US |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en_US |
dc.relation.journal | PLoS ONE | en_US |
dash.depositing.author | Shioda, Toshihiro | |
dc.date.available | 2013-10-17T18:08:51Z | |
dc.identifier.doi | 10.1371/journal.pone.0060889 | * |
dash.authorsordered | false | |
dash.contributor.affiliated | Yeh, Wei-Lan | |
dash.contributor.affiliated | Shioda, Toshihiro | |