Glycosylation-dependent mechanisms regulating ovarian tumor cell survival

糖基化依赖性调节卵巢肿瘤细胞存活的机制

• 批准号: 8718244
• 负责人: Susan L Bellis
• 金额: $ 27.93万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718244
• 关键词: Acute; Animal Model; Apoptosis; Apoptotic; Ascites; Automobile Driving; Binding; Biological Markers; Biological Response Modifiers; Biology; CD95 Antigens; Cancer Patient; Cancer cell line; Cell Death; Cell Survival; Cell surface; Cells; Cessation of life; Charge; Cisplatin; Clinical; Cytoprotection; Disease; Enzymes; Epithelial ovarian cancer; Epithelium; Equilibrium; Event; Galactose Binding Lectin; Galectin 3; Greater sac of peritoneum; Growth; Gynecologic; Human; Immune; Immunocompetent; Immunologic Surveillance; Immunotherapy; Implant; Incubated; Infiltration; Inflammatory; Integrins; Intervention; Knowledge; Ligands; Link; Liquid substance; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Minor; Molecular; Monitor; Mus; Neoplasm Metastasis; Ovarian; Papillary; Pathogenesis; Pathway interactions; Patients; Peritoneal; Pharmaceutical Preparations; Phenotype; Platinum; Polysaccharides; Prognostic Marker; Proteins; RNA Interference; Receptor Signaling; Recurrence; Research; Resistance; Role; ST6Gal I; Serous Cystadenocarcinoma; Sialic Acids; Sialyltransferases; Signal Transduction; Sorting - Cell Movement; Stimulus; Surface; TNF gene; TNFRSF1A gene; Therapeutic; Time; Tumor Biology; Tumor Cell Biology; Tumor Necrosis Factor Ligand Superfamily Member 6; Up-Regulation; Work; base; cancer cell; cell behavior; cell type; chemotherapy; cytokine; cytotoxic; glycosylation; glycosyltransferase; in vivo; innovation; neoplastic cell; novel; ovarian neoplasm; overexpression; prevent; prognostic; public health relevance; receptor; receptor function; receptor internalization; response; sialylation; sugar; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): An altered profile of surface glycans is a well-known feature of tumor cells; however the molecular mechanisms by which specific glycans and associated glycosyltransferases regulate tumor cell behavior remain elusive. Work from our group has determined that the ST6Gal-I sialyltransferase endows ovarian cancer (OC) cells with the ability to avoid apoptosis induced by multiple stimuli including galectins, death receptor activators and chemotherapeutic drugs. In this proposal we show for the first time that ST6Gal-I protein is upregulated in the great majority of human ovarian tumors, including the lethal papillary serous adenocarcinoma subtype. Upregulation of ST6Gal-I correspondingly causes hypersialylation of selected receptors including the ¿1 integrin, Fas and TNFR1. In paradigm-shifting mechanistic studies, we find that ST6Gal-I-mediated sialylation of Fas and TNFR1 prevents receptor internalization, causing a shift in the signaling of these receptors toward survival rather than apoptosis. Additionally, ST6Gal-I activity confers resistance to apoptotic galectin-3 and the chemotherapeutic, cisplatin. The central hypothesis of this proposal is that ST6Gal-I overexpression underlies two crucial factors contributing to OC lethality: tumor cell resistance to platinum-based chemotherapy (Aim 1), and OC cell protection against immune stimuli within the peritoneal tumor microenvironment (Aim 2), which is rich in gal-3 as well as ligands for Fas and TNFR1. Preliminary studies show that ST6Gal-I promotes OC cell survival within patient peritoneal ascites fluid; this finding is significant in that OC cells metastasize va peritoneal transit. AIM 1: ST6Gal-I-mediated receptor sialylation in chemoresistance. We will define molecular mechanisms responsible for ST6Gal-I's role in cisplatin resistance, and determine whether receptor sialylation controls chemoresistance within the intact tumor microenvironment. Efficacy of cisplatin treatment will be evaluated for orthotopic tumors established in mice from OC cells with differential ST6Gal-I expression, and in vivo delivery of RNAi will be used to implement therapeutic knockdown of ST6Gal-I to restore cisplatin sensitivity. ST6Gal-I will be quantified in chemosensitive vs. chemoresistant human tumors to assess its prognostic potential. AIM 2: Contribution of ST6Gal-I to tumor cell survival within the peritoneal microenvironment Mechanisms underlying ST6Gal-I-dependent OC cell survival within ascites will be elucidated, with a focus on gal-3/ ¿1 integrin, FasL/Fas, and TNF?/TNFR1 interactions. ST6Gal-I-mediated protection of OC cells from cytotoxic immune cells will be examined, and human ovarian tumors screened for an association between ST6Gal-I and immune cell infiltration. The growth of orthotopic tumors +/- ST6Gal-I will be monitored in immunocompetent mice. The studies will have impact by showing that ST6Gal-I is a master regulatory molecule controlling tumor/ microenvironmental interactions that regulate the balance between elimination vs. persistence of OC cells that drive tumor recurrence. Innovation lies in the elucidation of: (1) novel glycosylation-dependent tumor mechanisms, and (2) a new molecular player in OC pathogenesis and biomarker for patient chemoresistance.

描述（由适用提供）：表面聚糖的变化是肿瘤细胞的众所周知的特征；但是，特定的聚糖和相关糖基转移酶调节肿瘤细胞行为的分子机制仍然难以捉摸。我们小组的工作已经确定，ST6GAL-I乙烯基转移酶enders卵巢癌（OC）细胞具有避免多种刺激引起的凋亡的能力，其中包括甘脉蛋白，死亡受体激活剂和化学治疗药物。在这一建议中，我们首次表明，在大多数人类卵巢肿瘤中，包括致命的乳头状浆液腺癌亚型在内，ST6GAL-I蛋白已更新。 ST6GAL-I的上调相应地引起了选定接收器的超衰减，包括�1整合蛋白，FAS和TNFR1。在范式转移机械研究中，我们发现ST6GAL-I介导的Fas和TNFR1的溶解度阻止受体内在化，从而导致这些受体的信号转移向生存而不是细胞凋亡。另外，ST6GAL-I活性赋予对凋亡乳肠蛋白3和化学疗法顺铂的耐药性。该提议的核心假设是，ST6GAL-I的过表达是有助于OC致死性的两个关键因素：肿瘤细胞对基于铂的化学疗法的耐药性（AIM 1）和OC细胞对腹膜倾斜微型环境中的免疫抑制剂的保护（AIM 2），其中富含Gal-3和ligands and ligands and ligands and ligands and ligands and ligands and ligands。初步研究表明，ST6GAL-I促进患者腹膜腹水液体内的OC细胞存活。这一发现很重要，因为OC细胞转移了VA腹膜转移。 AIM 1：ST6GAL-I介导的受体在化学耐药性中的酶基化。我们将定义负责ST6GAL-I在顺铂耐药中的作用的分子机制，并确定受体溶解是否控制完整的肿瘤微环境中的化学耐药性。将评估顺铂治疗的功效，以通过具有差异性ST6GAL-I表达的OC细胞中建立的原位肿瘤进行评估，并将使用RNAi的体内递送来实施ST6GAL-I的热敲低以恢复顺铂敏感性。 ST6GAL-I将在化学敏感性与化学耐药的人类肿瘤中进行量化，以评估其预后潜力。目的2：将阐明ST6GAL-I对腹膜微环境机制内ST6GAL-I依赖性OC细胞在腹水中的生存的贡献，将阐明腹水中的OC细胞存活，重点关注Gal-3/€1整合蛋白，FASL/FAS，FASL/FAS和TNF？/tnf？/tnf？/TNFR1相互作用。将检查ST6GAL-I介导的OC细胞免受细胞毒性免疫细胞的保护，并筛选出人类卵巢肿瘤在ST6GAL-I和Immunocell浸润之间存在关联。原位肿瘤的生长+/- ST6GAL-I将在免疫能力小鼠中进行监测。这项研究将通过表明ST6GAL-I是控制肿瘤/微环境相互作用的主要调节分子，从而产生了影响，该分子调节了驱动肿瘤复发的OC细胞之间的平衡与持久性之间的平衡。创新在于阐明：（1）新型糖基化依赖性肿瘤机制，以及（2）OC发病机理和生物标志物的新分子玩家用于患者化学耐药。