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,也是第二大癌症原因
西方女性的死亡率。与大多数其他实体瘤的情况一样,转移和耐药性是肿瘤发生的主要原因。
主要死因。在约80%的BC病例中,由于PI 3 K-AKT通路的异常激活,
编码途径组分的基因的改变,例如Ras、Her 2、PTEN、PIK 3C和AKT。这
途径调节多种细胞过程以促进BC发育、生长、转移和药物治疗。
阻力因此,目前全世界正在进行100多项临床试验,以评估治疗效果。
PI 3 K和AKT抑制剂在BC中的疗效;然而,初始数据显示,
无效或经常导致产生耐药性和疾病复发。因此,鉴定
迫切需要另外的靶点和治疗组合。我们之前绘制了TRAF 2
TRAF 2 Ser-11磷酸化增强NF-κB活化,促进NF-κB活化。
癌细胞在细胞应激条件下的存活。最近,我们发现抑制BC中的AKT,
细胞导致TBK 1对TRAF 2的磷酸化增加,并且抑制AKT和TBK 1
在体外协同诱导BC细胞系凋亡并显著抑制异种移植BC肿瘤生长
in vivo. TBK 1及其同源物IKKε是丝氨酸/苏氨酸激酶,在65-70%的BC中过表达,
主要通过TRAF 2在Ser-11的直接磷酸化在BC细胞存活中起关键作用。在癌细胞中,
TRAF 2组成型募集有效的E3连接酶cIAP 1和cIAP 2(cIAP)到RIP 1,以催化其非经典的
泛素化,这不仅是必要的NF-κB活化,而且还为抑制RIP 1依赖的
凋亡和坏死性凋亡。通过一系列的功能分析,我们鉴定了一种肽(Tp-14),
TRAF 2与RIP 1相互作用并与AKT抑制协同诱导BC细胞凋亡,
过表达RIP 1。生物信息学分析显示TRAF 2和RIP 1在侵袭性BC中过表达,
且与预后不良显著相关。因此,我们假设联合抑制AKT和
TRAF 2磷酸化或与RIP 1的相互作用协同诱导过表达TRAF 2的BC细胞凋亡。
TRAF 2和RIP 1。为了验证这一假设,我们提出了以下具体目标。目标一确定
PI 3 K-AKT和TBK 1-TRAF 2通路之间的信号传导串扰机制,并鉴定生物标志物
预测BC细胞对AKT和TBK 1联合抑制的反应。目标二评估以下药物的治疗效果
在BC异种移植模型中的组合AKT和TBK 1抑制。目标三确定TRAF 2的阻断
与RIP 1的相互作用影响体外BC细胞存活和体内异种移植肿瘤生长。我们的提议将使
BC细胞对AKT抑制的抵抗机制的新发现,并确定了
联合抑制AKT和TRAF 2磷酸化或与RIP 1相互作用用于BC治疗。
项目成果
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HASEM HABELHAH其他文献
HASEM HABELHAH的其他文献
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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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