The roles of TRAF2 and RIP1 in breast cancer cell survival
TRAF2 和 RIP1 在乳腺癌细胞存活中的作用
基本信息
- 批准号:10619506
- 负责人:
- 金额:$ 34.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-15 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AKT inhibitionAffectApoptosisBioinformaticsBiological AssayBiological ModelsBreast Cancer CellBreast Cancer cell lineBreast Cancer therapyCancer EtiologyCancer cell lineCause of DeathCell LineCell SurvivalCell physiologyCellular StressCessation of lifeClinical TrialsDataDevelopmentDiagnosisDiseaseDrug resistanceExhibitsGenesGoalsGrowthGrowth FactorHarvestHistopathologyHomologous GeneIn VitroInduction of ApoptosisMalignant NeoplasmsMapsMediatingModelingMusNeoplasm MetastasisPIK3CG genePTEN genePathway interactionsPatient-derived xenograft models of breast cancerPeptidesPhosphorylationPhosphorylation SitePhosphotransferasesPlayPre-Clinical ModelPrognosisProtein-Serine-Threonine KinasesProto-Oncogene Proteins c-aktRIPK1 geneRecurrent diseaseReportingResistanceResistance developmentRoleSeriesSerineSignal TransductionSmall Interfering RNASolid NeoplasmTBK1 geneTNF geneTRAF2 geneTestingTherapeuticTreatment EfficacyUbiquitinationWomanXenograft ModelXenograft procedureanticancer researchbiomarker identificationcancer cellderepressionglycogen synthase kinase 3 betain vivoinhibitorkinase inhibitorknock-downmalignant breast neoplasmmortalitynovel therapeutic interventionoverexpressionpatient derived xenograft modelpredictive markerrecruitresponsesynergismtooltreatment responsetumortumor growthtumor xenograftubiquitin-protein ligase
项目摘要
Breast cancer (BC) is the most frequently diagnosed malignancy and the second leading cause of cancer
mortality in Western women. As is the case for most other solid tumors, metastasis and drug resistance are the
main causes of death. In ~80% of BC cases, the PI3K-AKT pathway is aberrantly activated, due to the
alterations in genes encoding the pathway components, such as Ras, Her2, PTEN, PIK3C and AKT. This
pathway regulates multiple cellular processes to promote BC development, growth, metastasis, and drug
resistance. Consequently, over 100 clinical trials are currently underway worldwide to evaluate the therapeutic
efficacy of PI3K and AKT inhibitors in BC; however, initial data revealed that inhibition of this pathway is either
not effective or often results in development of resistance and relapse of the disease. Thus, identification of
additional targets and therapeutic combinations are urgently needed. We previously mapped TRAF2
phosphorylation sites and reported that TRAF2 Ser-11 phosphorylation enhances NF-κB activation to promote
cancer cell survival under conditions of cellular stresses. Recently, we discovered that inhibition of AKT in BC
cells leads to increased phosphorylation of TRAF2 by TBK1, and that inhibition of both AKT and TBK1
synergistically induces apoptosis in BC cell lines in vitro and significantly suppresses xenograft BC tumor growth
in vivo. TBK1 and its close homologue IKKε are serine/threonine kinases overexpressed in 65-70% of BC and
play critical roles in BC cell survival mainly by direct phosphorylation of TRAF2 at Ser-11. In cancer cells,
TRAF2 constitutively recruits potent E3 ligases cIAP1 and cIAP2 (cIAPs) to RIP1 to catalyze its noncanonical
ubiquitination, which is not only essential for NF-κB activation but also for the suppression of RIP1-dependent
apoptosis and necroptosis. Through a series of functional assays, we identified a peptide (Tp-14) that blocks
TRAF2 interaction with RIP1 and synergizes with AKT inhibition to induce apoptosis in BC cells that
overexpress RIP1. Bioinformatic analyses revealed that TRAF2 and RIP1 are overexpressed in invasive BC,
and significantly correlate with poor prognosis. Thus, we hypothesize that combined inhibition of AKT and
TRAF2 phosphorylation or interaction with RIP1 synergistically induce apoptosis in BC cells that overexpress
TRAF2 and RIP1. To test this hypothesis, we propose the following specific aims. Aim-1. Determine the
mechanisms of signaling crosstalks between the PI3K-AKT and TBK1-TRAF2 pathways and identify biomarkers
that predict BC cell response to combined AKT and TBK1 inhibition. Aim-2. Evaluate the therapeutic efficacy of
combined AKT and TBK1 inhibition in BC xenograft models. Aim-3. Determine how blockade of TRAF2
interaction with RIP1 affects BC cell survival in vitro and xenograft tumor growth in vivo. Our proposals will shed
new lights on the mechanisms underlying BC cell resistance to AKT inhibition and identify biomarkers for
combined inhibition of AKT and TRAF2 phosphorylation or interaction with RIP1 for BC therapy.
乳腺癌(BC)是最常见的恶性肿瘤,也是第二大癌症病因
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('HASEM HABELHAH', 18)}}的其他基金
The roles of TRAF2 and RIP1 in breast cancer cell survival
TRAF2 和 RIP1 在乳腺癌细胞存活中的作用
- 批准号:
10363270 - 财政年份:2022
- 资助金额:
$ 34.51万 - 项目类别:
Therapeutic efficacies of neutrophil elastase and RIP1 inhibitors in acute lung injury
中性粒细胞弹性蛋白酶和RIP1抑制剂治疗急性肺损伤的疗效
- 批准号:
10311120 - 财政年份:2020
- 资助金额:
$ 34.51万 - 项目类别:
HtrA2-mediated RIP1 cleavage regulates neuronal inflammation and death
HtrA2介导的RIP1裂解调节神经元炎症和死亡
- 批准号:
9371476 - 财政年份:2017
- 资助金额:
$ 34.51万 - 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 裂解 RIP1 对于 TRAIL 诱导的 NF-kB 激活至关重要
- 批准号:
8033152 - 财政年份:2010
- 资助金额:
$ 34.51万 - 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 对 RIP1 的切割对于 TRAIL 诱导的 NF-kB 激活至关重要
- 批准号:
8403529 - 财政年份:2010
- 资助金额:
$ 34.51万 - 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 裂解 RIP1 对于 TRAIL 诱导的 NF-kB 激活至关重要
- 批准号:
7887290 - 财政年份:2010
- 资助金额:
$ 34.51万 - 项目类别:
RIP1 Cleavage by Caspase-8 is Essential for TRAIL-induced NF-kB Activation
Caspase-8 裂解 RIP1 对于 TRAIL 诱导的 NF-kB 激活至关重要
- 批准号:
8206767 - 财政年份:2010
- 资助金额:
$ 34.51万 - 项目类别:
Regulation of TRAF2 Activity in Normal and Tumor Cells
正常细胞和肿瘤细胞中 TRAF2 活性的调节
- 批准号:
7339874 - 财政年份:2006
- 资助金额:
$ 34.51万 - 项目类别:
Regulation of TRAF2 Activity in Normal and Tumor Cells
正常细胞和肿瘤细胞中 TRAF2 活性的调节
- 批准号:
7187428 - 财政年份:2006
- 资助金额:
$ 34.51万 - 项目类别:
Regulation of TRAF2 Activity in Normal and Tumor Cells
正常细胞和肿瘤细胞中 TRAF2 活性的调节
- 批准号:
7034445 - 财政年份:2006
- 资助金额:
$ 34.51万 - 项目类别:
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