权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The role for alcohol-induced Golgi disorganization in the progression of prostate cancer

酒精引起的高尔基体紊乱在前列腺癌进展中的作用

基本信息

批准号：
10459629
负责人：
Armen Petrosyan
金额：
$ 34.31万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-02 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459629
关键词：
ATF6 gene Ablation Address Alcohol abuse Alcohol consumption Alcoholism Alcohols Androgen Receptor Animal Model Attenuated Biology Cancer Etiology Cancer Patient Carcinogenesis Mechanism Case-Control Studies Cell Survival Cell surface Cells Cessation of life Chronic Clinical Coat Protein Complex I Consensus Cytoplasm Data Development Diagnosis Dimerization Docking Endoplasmic Reticulum Enzymes Ethanol Event Glycogen Synthase Kinases Goals Golgi Apparatus Growth HDAC6 gene Heat-Shock Proteins 90 Heavy Drinking Hepatocyte Impairment In Vitro Incidence Integrins LNCaP Lead Light Link Literature Malignant Neoplasms Malignant neoplasm of prostate Mediating Molecular Motor Mus Neoplasm Metastasis Nonmuscle Myosin Type IIA Oncogenic Organ Outcome Study Pathway interactions Peptide Hydrolases Phenotype Phosphorylation Phosphotransferases Physiological Polysaccharides Population Study Prostate Prostatic Neoplasms Proteins Reporting Research Risk Factors Role Sampling Signal Pathway Stress Testing Therapeutic Therapeutic Intervention Transactivation Tumor Promotion United States Vesicle Xenograft procedure advanced prostate cancer alcohol abstinence alcohol abuse therapy alcohol effect alcohol prevention androgen sensitive base biological adaptation to stress carcinogenesis castration resistant prostate cancer chronic alcohol ingestion endoplasmic reticulum stress epidemiology study experimental study glycosylation glycosyltransferase in vivo innovation insight knock-down macrogolgin matriptase men migration misfolded protein mortality non-muscle myosin novel overexpression prevent prostate cancer cell prostate cancer cell line prostate cancer progression protein transport response sensor tumor tumor initiation tumor progression

项目摘要

ABSTRACT Chronic alcohol abuse and alcoholism are considered risk factors for prostate cancer (PCa) progression, but the mechanism is unknown. The current project will address an important question raised by clinicians: whether alcohol abstinence is an important therapeutic intervention in PCa. Previously, we found that: (1) fragmentation of the Golgi complex correlates with the progression of PCa; (2) ethanol (EtOH) induces Golgi disorganization that is caused by the impaired dimerization of the largest Golgi matrix protein giantin, which, in turn, alters intra-Golgi localization of some Golgi proteins. Indeed, we recently observed that in androgen-responsive PCa cells, EtOH- induced Golgi fragmentation leads to translocation of glycogen synthase kinase β (GSK3β) from the Golgi to the cytoplasm, followed by the activation of HDAC6-HSP90-AR pathway. Additionally, we reported that non-muscle myosin IIA (NMIIA) motor protein forces EtOH-induced Golgi disruption. Also, alcohol induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR), which are the known drivers of PCa advancement; however, the mechanism of EtOH-induced UPR in cancer remains largely uncovered. Here, we found that in low passage LNCaP cells, one of the UPR sensor, ATF6, is cleaved in Golgi by S1P and S2P proteases; however, EtOH treatment alters the Golgi localization of S1P and S2P, trapping them in the ER and facilitating ATF6 transactivation. Further, EtOH induces translocation of the glycosyltransferase MGAT3 from the Golgi to the cytoplasm followed by its degradation. However, MGAT5, the enzyme that competes with MGAT3 for N-glycan branching, is still retained in the Golgi. This results in MGAT5-mediated glycosylation of pro-metastatic proteins (including matriptase and integrins) and their overexpression at the cell surface. Finally, we detected that loss of NMIIA function prevents alcohol-induced Golgi fragmentation in PCa cells. This, in turn, recovers MGAT3’s intra- Golgi localization and reduces the expression of integrins. In light of these facts, we propose to test the hypothesis that alcohol accelerates PCa progression through Golgi fragmentation, which: (a) enhances ER stress response via induction of ATF6-mediated UPR, and (b) stimulates expression of pro-metastatic proteins over their abnormal MGAT5-mediated glycosylation. Hence, targeting alcohol-induced Golgi fragmentation is therapeutically important. The three specific aims of the proposed study are to: 1) elucidate the mechanism of alcohol-induced activation of ER stress by determining how alcohol metabolites induce translocation of Golgi localized S1P and S2P proteases to the ER; 2) examine the role of EtOH-induced MGAT5-mediated glycosylation in the progression of PCa; and 3) examine whether inhibition or knockdown of NMIIA prevents EtOH-induced Golgi fragmentation and attenuates the aggressive phenotype of PCa cells. The approach will include a variety of in vitro and in vivo experiments using EtOH-treated PCa cell lines, animal models and clinical samples from alcohol consuming PCa patients. The accomplishment of the goal of the proposed study would expand our understanding of the basic biology of PCa carcinogenesis, and elucidate the mechanisms of alcohol's tumor promotion action.

摘要