StarD5, a protein that translocates cholesterol to the plasma membrane, is a novel target for Colon Cancer

StarD5 是一种将胆固醇转移至质膜的蛋白质，是结肠癌的新靶标

• 批准号: 9891217
• 负责人: Bhaumik B Patel
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891217
• 关键词: Affect; Animal Cancer Model; Antineoplastic Agents; Brain; CXCR4 gene; Cancer Cell Growth; Cancer Control; Cancer Etiology; Carrier Proteins; Cell membrane; Cells; Cessation of life; Chemicals; Chemotherapy-Oncologic Procedure; Cholesterol; Cholesterol Homeostasis; Clinical; Colon; Colon Carcinoma; Colorectal Cancer; Data; Disease remission; Dose; Drug Kinetics; Epidermal Growth Factor Receptor; FDA approved; Fluorouracil; Frequencies; Generations; Goals; Growth; Growth Factor; HCT116 Cells; HT29 Cells; Human; In Vitro; Insulin-Like-Growth Factor I Receptor; Intestines; Intracellular Transport; Knock-out; Laboratories; Lead; Lipids; Liver; Malignant Neoplasms; Mammalian Cell; Manuscripts; Membrane; Membrane Fluidity; Molecular; Morphology; Movement; Mucous Membrane; Mus; Obesity; Organ; Organoids; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Platinum Compounds; Play; Property; Proteins; Receptor Signaling; Regulation; Relapse; Resistance; Role; Schedule; Signal Transduction; Structure; Testing; Thinness; Tissues; Toxic effect; Treatment Efficacy; Tyrosine Phosphorylation; Xenograft procedure; biophysical properties; cancer cell; cancer initiation; cancer seeding; cancer stem cell; cancer therapy; cell growth; chemotherapeutic agent; chemotherapy; colorectal cancer treatment; fluidity; genetic variant; in vivo; innovation; insight; knock-down; neoplastic cell; novel; novel anticancer drug; overexpression; oxaliplatin; panitumumab; progenitor; prognostic significance; self-renewal; small hairpin RNA; small molecular inhibitor; stem; steroidogenic acute regulatory protein; targeted agent; targeted cancer therapy; targeted treatment; therapeutic target; therapy resistant; tumor; tumor growth; tumor progression

Colorectal cancer (CRC) is the third leading cause of cancer death in the US. It is difficult to cure CRC because majority of the existing therapies fail to significantly obliterate seeds of cancer called `cancer stem cells (CRCSCs). Cellular cholesterol metabolism is a single most important target for CRCSCs. However, existing therapies that target this pathway, e.g. statins fail to significantly inhibit cholesterol levels in the cells due to redundant mechanisms that govern cholesterol levels in cancer cells. However, cholesterol utilization is regulated by select group of specific cholesterol transport proteins, which if targeted, can have critical effect on plasma membrane (PM) biophysical properties of CRC cells. We have identified a cholesterol transport protein called StarD5, which is the only known mammalian protein that regulates cholesterol transport to cell membrane. StarD5 is significantly overexpressed in human colon cancer tissues and particularly in colon CRCSCs. Inhibition of StarD5 resulted in significant inhibition of colon CSCs in vitro and in vivo, as well as cholesterol contents in PM resulting in increased PM fluidity and robust inhibition of Insulin-like growth factor-1 receptor (IGF1R) and epidermal growth factor receptor (EGFR) signaling. We propose to examine, in detail, the significance of StarD5 overexpression on colon cancer initiation, progression, and patient outcomes as well as impact of StarD5 modulation on CRCSC phenotype in human CRCSCs (Aim 1). We would also like to understand mechanisms of how StarD5 inhibition regulates CSCs. To that end, we propose to determine the effect of StarD5 inhibition on PM fluidity, influx of platinum agents, and growth factor signaling initiated in PM (Aim 2). Moreover, we plan to examine the efficacy of small molecular inhibitors of StarD5 (SD5i) on CRCSC phenotype using primary human colon spheroids as well as determine their efficacy of in combination with FDA-approved chemotherapy and targeted therapy (panitumumab) against advanced animal models of CSCs (Aim 3). The studies will provide novel insight into how alternation in membrane cholesterol regulates cancer growth, and provide a novel class of target for cancer therapies that may lead to long-term remission and/or cure by targeting therapy resistant CRCSCs.

结直肠癌(CRC)是美国癌症死亡的第三大原因。难治性结直肠癌 因为大多数现有的治疗方法都不能显著消除癌症的种子，这就是所谓的癌症干细胞 细胞(CRCSCs)。细胞胆固醇代谢是CRCSCs最重要的靶点。然而， 针对这一途径的现有疗法，例如他汀类药物，未能显著抑制细胞中的胆固醇水平 由于控制癌细胞中胆固醇水平的多余机制。然而，胆固醇的利用率是 由特定的一组特定的胆固醇运输蛋白调节，如果有靶向，可能对 结直肠癌细胞的质膜生物物理特性。我们发现了一种胆固醇转运蛋白 被称为StarD5，它是唯一已知的哺乳动物蛋白质，调节胆固醇向细胞的运输 薄膜。StarD5在人结肠癌组织中显著过表达，尤其是在结肠组织中 CRCSCs。抑制StarD5对体外和体内的结肠CSCs均有显著抑制作用 PM中的胆固醇含量导致PM流动性增加和胰岛素样生长因子-1的强烈抑制 受体(IGF1R)和表皮生长因子受体(EGFR)信号转导。我们建议详细研究， StarD5过表达在结肠癌发生、发展和患者预后中的意义 以及StarD5调控对人CRCSC表型的影响(目标1)。我们会 也想了解StarD5抑制如何调节CSCs的机制。为此，我们建议 确定StarD5抑制对PM流动性、铂类药物内流和生长因子信号的影响 在下午开始(目标2)。此外，我们计划检查StarD5小分子抑制剂的疗效 (SD5I)对原代人结肠球体CRCSC表型的影响 联合FDA批准的化疗和靶向治疗(Panitumab)治疗晚期 CSCs动物模型(目的3)。这些研究将提供新的洞察力，了解交替是如何发生的 膜胆固醇调节肿瘤生长，为癌症治疗提供了一类新的靶点 这可能会通过靶向治疗耐药的CRCSCs而导致长期缓解和/或治愈。