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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：
HASEM HABELHAH
金额：
$ 34.51万
依托单位：
UNIVERSITY OF IOWA
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：
https://reporter.nih.gov/project-details/10619506
关键词：
AKT inhibition Affect Apoptosis Bioinformatics Biological Assay Biological Models Breast Cancer Cell Breast Cancer cell line Breast Cancer therapy Cancer Etiology Cancer cell line Cause of Death Cell Line Cell Survival Cell physiology Cellular Stress Cessation of life Clinical Trials Data Development Diagnosis Disease Drug resistance Exhibits Genes Goals Growth Growth Factor Harvest Histopathology Homologous Gene In Vitro Induction of Apoptosis Malignant Neoplasms Maps Mediating Modeling Mus Neoplasm Metastasis PIK3CG gene PTEN gene Pathway interactions Patient-derived xenograft models of breast cancer Peptides Phosphorylation Phosphorylation Site Phosphotransferases Play Pre-Clinical Model Prognosis Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt RIPK1 gene Recurrent disease Reporting Resistance Resistance development Role Series Serine Signal Transduction Small Interfering RNA Solid Neoplasm TBK1 gene TNF gene TRAF2 gene Testing Therapeutic Treatment Efficacy Ubiquitination Woman Xenograft Model Xenograft procedure anticancer research biomarker identification cancer cell derepression glycogen synthase kinase 3 beta in vivo inhibitor kinase inhibitor knock-down malignant breast neoplasm mortality novel therapeutic intervention overexpression patient derived xenograft model predictive marker recruit response synergism tool treatment response tumor tumor growth tumor xenograft ubiquitin-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