Show simple item record

dc.contributor.authorConti, A
dc.contributor.authorMajorini, MT
dc.contributor.authorElliott, R
dc.contributor.authorAshworth, A
dc.contributor.authorLord, CJ
dc.contributor.authorCancelliere, C
dc.contributor.authorBardelli, A
dc.contributor.authorSeneci, P
dc.contributor.authorWalczak, H
dc.contributor.authorDelia, D
dc.contributor.authorLecis, D
dc.date.accessioned2016-09-14T09:32:40Z
dc.date.issued2015-05
dc.identifier.citationOncotarget, 2015, 6 (13), pp. 10994 - 11008
dc.identifier.issn1949-2553
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/107
dc.identifier.eissn1949-2553en_US
dc.identifier.doi10.18632/oncotarget.3552en_US
dc.description.abstractKRAS is mutated in about 20-25% of all human cancers and especially in pancreatic, lung and colorectal tumors. Oncogenic KRAS stimulates several pro-survival pathways, but it also triggers the trans-activation of pro-apoptotic genes. In our work, we show that G13D mutations of KRAS activate the MAPK pathway, and ERK2, but not ERK1, up-regulates Noxa basal levels. Accordingly, premalignant epithelial cells are sensitized to various cytotoxic compounds in a Noxa-dependent manner. In contrast to these findings, colorectal cancer cell sensitivity to treatment is independent of KRAS status and Noxa levels are not up-regulated in the presence of mutated KRAS despite the fact that ERK2 still promotes Noxa expression. We therefore speculated that other survival pathways are counteracting the pro-apoptotic effect of mutated KRAS and found that the inhibition of AKT restores sensitivity to treatment, especially in presence of oncogenic KRAS. In conclusion, our work suggests that the pharmacological inhibition of the pathways triggered by mutated KRAS could also switch off its oncogene-activated pro-apoptotic stimulation. On the contrary, the combination of chemotherapy to inhibitors of specific pro-survival pathways, such as the one controlled by AKT, could enhance treatment efficacy by exploiting the pro-death stimulation derived by oncogene activation.
dc.formatPrint
dc.format.extent10994 - 11008
dc.languageeng
dc.language.isoeng
dc.subjectMammary Glands, Human
dc.subjectCells, Cultured
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectProto-Oncogene Proteins c-bcl-2
dc.subjectAntineoplastic Agents
dc.subjectBlotting, Western
dc.subjectFlow Cytometry
dc.subjectApoptosis
dc.subjectCell Proliferation
dc.subjectMAP Kinase Signaling System
dc.subjectPhosphorylation
dc.subjectMutation
dc.subjectProto-Oncogene Proteins p21(ras)
dc.subjectHigh-Throughput Screening Assays
dc.titleOncogenic KRAS sensitizes premalignant, but not malignant cells, to Noxa-dependent apoptosis through the activation of the MEK/ERK pathway.
dc.typeJournal Article
dcterms.dateAccepted2015-02-21
rioxxterms.versionofrecord10.18632/oncotarget.3552
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2015-05en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfOncotarget
pubs.issue13
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
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/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume6en_US
pubs.embargo.termsNot known
icr.researchteamGene Functionen_US
dc.contributor.icrauthorLord, Christopheren


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record