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dc.contributor.authorSmith, MP
dc.contributor.authorFerguson, J
dc.contributor.authorArozarena, I
dc.contributor.authorHayward, R
dc.contributor.authorMarais, R
dc.contributor.authorChapman, A
dc.contributor.authorHurlstone, A
dc.contributor.authorWellbrock, C
dc.date.accessioned2018-08-07T11:02:02Z
dc.date.issued2013-01
dc.identifier1
dc.identifier.citationJNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2013, 105 pp. 33 - 46
dc.identifier.issn0027-8874
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2280
dc.identifier.eissn1460-2105
dc.identifier.doi10.1093/jnci/djs471
dc.description.abstractThe mitogen-activated proteinkinase pathway consisting of the kinases RAF, MEK, and ERK is central to cell proliferation and survival and is deregulated in more than 90% of melanomas. MEK inhibitors are currently trialled in the clinic, but despite efficient target inhibition, cytostatic rather than cytotoxic activity limits their efficacy. We assessed the cytotoxicity to MEK inhibitors (PD184352 and selumetinib) in melanoma cells by toluidine-blue staining, caspase 3 cleavage, and melanoma-sphere growth. Western blotting and quantitative real-time polymerase chain reaction were applied to determine SMAD-specific E3 ubiquitin protein ligase 2 (SMURF2), PAX3, and MITF expression. Human melanoma samples (n 77) from various stages were analyzed for SMURF2 and PAX3 expression. RNA interference was performed to target SMURF2 during MEK inhibition in vivo in melanoma xenografts in mice and zebrafish. All statistical tests were two-sided. Activation of transforming growth factor (TGF-) signalling sensitized melanoma cells to the cytotoxic effects of MEK inhibition. Melanoma cells resistant to the cytotoxic effects of MEK inhibitors counteracted TGF- signalling through overexpression of the E3 ubiquitin ligase SMURF2, which resulted in increased expression of the transcription factors PAX3 and MITF. High MITF expression protected melanoma cells against MEK inhibitor cytotoxicity. Depleting SMURF2 reduced MITF expression and substantially lowered the threshold for MEK inhibitorinduced apoptosis. Moreover, SMURF2 depletion sensitized melanoma cells to the cytotoxic effects of selumetinib, leading to cell death at concentrations approximately 100-fold lower than the concentration required to induce cell death in SMURF2-expressing cells. Mice treated with selumetinib alone at a dosage of 10mg/kg body weight once daily produced no response, but in combination with SMURF2 depletion, selumetinib suppressed tumor growth by 97.9% (95% confidence interval 38.65% to 155.50%, P .005). Targeting SMURF2 may be a novel therapeutic approach for increasing the antitumor efficacy of MEK inhibitors.
dc.format.extent33 - 46
dc.languageeng
dc.language.isoeng
dc.publisherOXFORD UNIV PRESS INC
dc.titleEffect of SMURF2 Targeting on Susceptibility to MEK Inhibitors in Melanoma
dc.typeJournal Article
rioxxterms.versionofrecord10.1093/jnci/djs471
rioxxterms.licenseref.startdate2013-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
pubs.notesaffiliation: Wellbrock, C (Reprint Author), Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. Smith, Michael P.; Ferguson, Jennifer; Arozarena, Imanol; Chapman, Anna; Hurlstone, Adam; Wellbrock, Claudia, Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England. Hayward, Robert; Marais, Richard, Inst Canc Res, Chester Beatty Labs, Div Canc Biol, London SW3 6JB, England. keywords-plus: BREAST-CANCER CELLS; AZD6244 ARRY-142886; TGF-BETA; ACQUIRED-RESISTANCE; UBIQUITIN LIGASES; LINEAGE SURVIVAL; MASTER REGULATOR; RAF INHIBITION; UP-REGULATION; BRAF GENE research-areas: Oncology web-of-science-categories: Oncology author-email: [email protected] orcid-numbers: Hurlstone, Adam/0000-0001-5260-9457 Smith, Michael/0000-0002-5980-7840 Marais, Richard/0000-0001-7484-4183 funding-acknowledgement: Cancer Research UK [C11591/A10202, C11876/A12724]; BBSRC [FA01472 FLS]; Manchester University; Cancer Research UK [17240, 19279] funding-text: This work was supported by Cancer Research UK (C11591/A10202 and C11876/A12724). MS is funded by the BBSRC (FA01472 FLS) and the Alumni Fund of the Manchester University. number-of-cited-references: 48 times-cited: 44 usage-count-last-180-days: 0 usage-count-since-2013: 10 journal-iso: JNCI-J. Natl. Cancer Inst. doc-delivery-number: 066JN unique-id: ISI:000313217100008 oa: gold_or_bronze da: 2018-08-06
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.volume105
pubs.embargo.termsNot known
icr.researchteamSignal Transductionen_US
dc.contributor.icrauthorMarais, Richard Malcolmen


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