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，是结肠癌的新靶点

• 批准号: 10115516
• 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/10115516
• 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; Chemoresistance; 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; 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; chemotherapeutic agent; chemotherapy; colorectal cancer treatment; efficacy evaluation; 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; stem cell growth; stem cell self renewal; 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主要原因。很难治愈CRC 因为大多数现有疗法未能显着消除称为癌症的癌症种子 细胞（CRCSC）。细胞胆固醇代谢是CRCSC的最重要靶标。然而， 针对此途径的现有疗法，例如他汀类药物无法显着抑制细胞中的胆固醇水平 由于冗余机制，这些机制控制了癌细胞中胆固醇水平。但是，胆固醇的利用是 由精选的特定胆固醇转运蛋白的选定组调节，如果有针对性，则可能对 CRC细胞的质膜（PM）生物物理特性。我们已经确定了胆固醇的转运蛋白 称为stard5，这是唯一已知的哺乳动物蛋白，可调节胆固醇转运到细胞 膜。 Stard5在人类结肠癌组织中，特别是在结肠中明显过表达 CRCSC。 Stard5的抑制作用导致体外和体内结肠CSC的显着抑制作用，以及 PM中的胆固醇含量导致PM的流动性升高和胰岛素样生长因子1 受体（IGF1R）和表皮生长因子受体（EGFR）信号传导。我们建议详细检查 Stard5过表达对结肠癌开始，进展和患者预后的重要性 以及Stard5调制对人CRCSC中CRCSC表型的影响（AIM 1）。我们会的 还喜欢了解Stard5抑制如何调节CSC的机制。为此，我们建议 确定stard5抑制对PM流动性，铂剂流入和生长因子信号的影响 在PM中启动（AIM 2）。此外，我们计划检查Stard5的小分子抑制剂的功效 （SD5I）使用原代人类结肠球体在CRCSC表型上，并确定其效果 与FDA批准的化学疗法和靶向疗法（Panitumumab）结合使用 CSC的动物模型（AIM 3）。这些研究将为如何交替提供新的见解 膜胆固醇调节癌症的生长，并为癌症疗法提供新的靶标 这可能会通过靶向抗治疗CRCSC来导致长期缓解和/或治愈。