Role of B-arrestins in bladder cancer progression and response to chemotherapy

B-抑制蛋白在膀胱癌进展和化疗反应中的作用

• 批准号: 10815683
• 负责人: Bal L Lokeshwar
• 金额: --
• 依托单位: CHARLIE NORWOOD VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10815683
• 关键词: ARRB2; Acceleration; Adjuvant Chemotherapy; Archives; Arrestin Beta 1; Arrestins; Basal Cell; Bladder; Bladder Neoplasm; Bladder Tissue; CRISPR/Cas technology; Cancer Cell Growth; Cancer Model; Cancer Patient; Cancer cell line; Cell Proliferation; Cells; Chemoresistance; Cisplatin; Clinical; Combination Drug Therapy; Complex; Databases; Disease; Disease-Free Survival; Eligibility Determination; Enhancers; Epithelial Cells; Exhibits; Freezing; G-Protein-Coupled Receptors; Growth; Heterogeneity; Human; In Vitro; Incidence; Invaded; Investigation; Knock-out; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Messenger RNA; Metabolism; Modeling; Molecular Profiling; Morbidity - disease rate; Muscle; Myomatous neoplasm; Neoadjuvant Therapy; Neoplasm Metastasis; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Prediction of Response to Therapy; Prognostic Marker; Property; Proteins; Recurrence; Refractory; Reporting; Research; Research Personnel; Resistance; Role; Signal Transduction; Specimen; Testing; Tetrahydrouridine; The Cancer Genome Atlas; Tissues; Tobacco-Associated Carcinogen; Treatment Cost; Treatment Failure; Tumor Tissue; United States; Urogenital Cancer; Veterans; Work; Xenograft Model; biomarker validation; cancer cell; cancer diagnosis; cancer invasiveness; cancer stem cell; carcinogenesis; cell motility; chemokine receptor; chemotherapy; cytotoxicity; efficacy testing; environmental tobacco smoke exposure; gemcitabine; high risk; improved; individualized medicine; inhibitor; knockout gene; male; member; molecular marker; mortality; muscle invasive bladder cancer; neoplastic cell; overexpression; patient derived xenograft model; pre-clinical; predict clinical outcome; prospective; refractory cancer; response; small hairpin RNA; stem cell biomarkers; treatment and outcome; treatment response; tumor; tumor growth; tumor progression; tumor xenograft; tumorigenesis

Bladder cancer is the most expensive cancer to treat. Frequent recurrence and treatment refractoriness are the most common causes of morbidity and high cost of treatment of this disease. Males are three times more likely to develop bladder cancer. Therefore, the United States Veterans are at higher risk of developing bladder cancer. The high-grade, muscle invasive bladder cancers are difficult to treat and neoadjuvant and adjuvant chemotherapies have only modest benefits for overall survival. The investigators identified a pair of molecular markers that potentially determine response to chemotherapy, especially towards the Gemcitabine + Cisplatin chemotherapy combination. The markers β-Arrestin 1 (BARR1) and β-Arrestin 2 (BARR2) are members of the intracellular signaling complex triggered by chemokine receptors. The research group investigated muscle invasive bladder cancer tissues and found that BARR1 and BARR2 expressions are associated with treatment failure and metastasis. Further, in vitro studies using established bladder cancer cell lines showed an inverse correlation between BARR2 levels and the cancer stem cell phenotype, metastatic potential, and resistance to Gemcitabine induced cytotoxicity. Conversely, BARR1 expression correlated with metastasis and cancer stem cell properties. The principal hypothesis of this project is BARR1 and BARR2 are regulators of BC cell growth, differentiation into basal or luminal cell phenotype, and BC cell motility. BARR1 and BARR2 regulate malignant progressions, such as muscle invasion, metastasis, and resistance to chemotherapy drugs. Three specific aims are proposed: 1. To investigate the mechanism by which BARR1 and BARR2 regulate BC growth, cancer stem cell phenotype, and invasive/metastatic potential; 2. To investigate whether modulation of the levels of BARR1 and BARR2 alters the response to Gem treatment in preclinical BC models. Also, test the potential of tetrahydrouridine, an inhibitor of intracellular Gemcitabine metabolism, to sensitize chemotherapy-resistant Patient-derived bladder tumor xenografts (PDX) towards Gemcitabine; 3. To investigate the potential of BARR1 and BARR2 expression as a predictor of chemotherapy response and clinical outcome in MIBC. The investigators consider the high impact of this project on improving the prediction of treatment-response in high- grade bladder cancers as well as therapy response using a combination of a non-toxic drug and an established chemotherapy drug. The proposed studies have the potential to improve bladder cancer treatment and outcome for U.S. Veterans.

膀胱癌是治疗费用最高的癌症，复发率高，治疗无效， 最常见的发病原因和这种疾病的治疗费用高。男性比女性 患上膀胱癌因此，美国退伍军人患膀胱炎的风险较高。 癌高级别、肌层浸润性膀胱癌难以治疗，新辅助治疗和辅助治疗都很困难。 化疗对总生存期只有适度的益处。研究人员发现了一对分子 可能决定化疗应答的标志物，尤其是吉西他滨+顺铂 联合化疗标志物β-抑制蛋白1（BARR 1）和β-抑制蛋白2（BARR 2）是由β-抑制蛋白1（BARR 1）和β-抑制蛋白2（BARR 2）组成的蛋白质组的成员。 由趋化因子受体触发的细胞内信号复合物。研究小组调查了肌肉 浸润性膀胱癌组织，并发现BARR 1和BARR 2表达与治疗相关 失败和转移。此外，使用已建立的膀胱癌细胞系的体外研究显示， BARR 2水平与癌症干细胞表型、转移潜能和对肿瘤干细胞的抗性之间的相关性。 吉西他滨诱导的细胞毒性。相反，BARR 1表达与转移和癌干细胞相关， 细胞特性。本项目的主要假设是BARR 1和BARR 2是BC细胞生长的调节因子， 分化成基底或腔细胞表型，以及BC细胞运动性。BARR 1和BARR 2调节恶性肿瘤 进展，如肌肉浸润、转移和对化疗药物的耐药性。三个具体 提出了以下目标：1.为了研究BARR 1和BARR 2调节BC生长的机制， 干细胞表型和侵袭/转移潜能; 2.为了研究是否调节了 BARR 1和BARR 2改变了临床前BC模型对Gem治疗的反应。同时，测试 四氢尿苷，细胞内吉西他滨代谢抑制剂，对化疗耐药 患者来源的膀胱肿瘤异种移植物（PDX）对吉西他滨的作用; 3.为了研究 BARR 1和BARR 2表达作为MIBC化疗反应和临床结果的预测因子的 研究人员认为，该项目对改善高血压患者治疗反应的预测具有重要影响， 分级膀胱癌以及使用无毒药物和已建立的 化疗药物拟议的研究有可能改善膀胱癌治疗， 美国退伍军人的结果。

项目成果

G protein βγ translocation to the Golgi apparatus activates MAPK via p110γ-p101 heterodimers.

• DOI: 10.1016/j.jbc.2021.100325
• 发表时间: 2021-01
• 期刊: The Journal of biological chemistry
• 作者: Khater M;Wei Z;Xu X;Huang W;Lokeshwar BL;Lambert NA;Wu G
• 通讯作者: Wu G

Promotion of epithelial hyperplasia by interleukin-8-CXCR axis in human prostate.

• DOI: 10.1002/pros.24026
• 发表时间: 2020-09
• 期刊: The Prostate
• 作者: Smith DK;Hasanali SL;Wang J;Kallifatidis G;Morera DS;Jordan AR;Terris MK;Klaassen Z;Bollag R;Lokeshwar VB;Lokeshwar BL
• 通讯作者: Lokeshwar BL