"Starve the Tumor Cells to Death": SLC6A14 as a Drug Target for Colon Cancer

“饿死肿瘤细胞”：SLC6A14作为结肠癌的药物靶点

• 批准号: 7963106
• 负责人: VADIVEL GANAPATHY
• 金额: $ 19.18万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7963106
• 关键词: Amino Acid Transporter; Amino Acids; Animal Model; Antineoplastic Agents; Apoptosis; Autophagocytosis; Azoxymethane; Biological; Cancer Center; Carbon; Carcinogens; Cell Cycle Arrest; Cells; Cessation of life; Chemicals; Code; Colon; Colon Carcinoma; Country; Coupled; Data; Dioxygenases; Disease; Drug Delivery Systems; Energy-Generating Resources; Essential Amino Acids; Genes; Genetic; Glucose; Glutamine; Goals; Growth; Human; Human Genome; Immune system; Knock-out; Knockout Mice; Laboratories; Lipids; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Membrane Potentials; Metabolism; Modeling; Molecular; Mus; Names; Nomenclature; Normal Cell; Normal tissue morphology; Nude Mice; Nutrient; Pharmaceutical Preparations; Philadelphia; Prodrugs; Production; Protein Biosynthesis; Proteins; Resistance; Source; Starvation; System; Testing; Therapeutic; Tryptophan; Up-Regulation; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; colon cancer cell line; driving force; fight against; in vivo; indoleamine; inhibitor/antagonist; malignant breast neoplasm; meetings; mouse model; neoplastic cell; nucleotide metabolism; nutrition; preclinical study; prevent; public health relevance; rapid growth; small hairpin RNA; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Colon cancer is the fourth most common cancer in this country. A wide variety of strategies are currently used for treatment of colon cancer, but none of them offers a permanent cure for the disease. New drug targets are sorely needed to succeed in the fight against this deadly disease. The current proposal focuses on one such drug target. It is a nutrient transporter, known as ATB0,+ encoded by the gene SLC6A14, which transports all essential amino acids as well as glutamine. This transporter is expressed only at low levels in normal tissues, but is induced several-fold in colon cancer. We hypothesize that tumor cells up-regulate ATB0,+ to meet their increasing demand for essential amino acids and glutamine. Since ATB0,+ transports all essential amino acids as well as glutamine, it is sufficient for the tumor cells to turn on a single gene to satisfy their amino acid needs. Since tumor cells rely on ATB0,+ as the primary source of essential amino acids and glutamine, blocking the transporter function may offer a logical strategy for cancer treatment. To validate this strategy, we propose three specific aims. Aim 1 is to evaluate the effects of shRNA-based silencing of ATB0,+ on the growth and progression of tumor with colon cancer cell lines in the nude mouse xenograft model. Here we will silence the transporter in colon cancer cell lines using a molecular biological approach and then examine the effects of the knockdown of the transporter on the growth and progression of tumor when these cells are xenografted into nude mice. Aim 2 is to evaluate the effects of ATB0,+ deletion on colon cancer by comparing the formation/progression of tumors induced by a carcinogen. Azoxymethane is used to induce colon cancer in mice. This is a genetic approach to delete the gene coding for the transporter. We predict that the transporter knockout mouse will be resistant to azoxymethane-induced colon cancer. Aim 3 is to evaluate the effects of pharmacological blockade of ATB0,+ with 1-methyl-L- tryptophan (1-MLT) on tumor growth in two different mouse models of colon cancer: a xenograft mouse model with human colon cancer cell lines and a carcinogen-induced colon carcinoma mouse model. This is a pharmacological approach to block the function of the transporter. We will use 1-MLT as a blocker of ATB0,+ to evaluate its ability to prevent colon cancer in these animal models. 1-MLT is also a potent inhibitor of indoleamine dioxygenase (IDO). Inhibition of IDO is known to potentiate the activity of immune system against tumors. Therefore, we predict that 1-MLT will function as an anti-cancer agent in vivo by acting through two different mechanisms: by blocking the tumor-specific nutrient transporter ATB0,+ thereby starving the tumor cells of essential amino acids, and also by inhibiting IDO thereby enhancing the activity of the immune system against the tumor. These studies will generate important information regarding the therapeutic potential of the cancer-specific amino acid transporter ATB0,+ for the treatment of colon cancer. PUBLIC HEALTH RELEVANCE: The goal of this project is to evaluate the therapeutic potential of a cancer-specific amino acid transporter, known as SLC6A14 or ATB0,+ in the treatment of colon cancer. Studies will involve the use of a xenograft mouse model with human colon cancer cell lines and a carcinogen- induced mouse model of colon cancer. The potential of the transporter as a drug target for treatment of colon cancer will be evaluated in these models with two approaches: a genetic approach with the deletion of ATB0,+ (Slc6a14-/- mouse) and a pharmacological approach with the use of a chemical blocker of ATB0,+

描述(申请人提供)：结肠癌是这个国家第四常见的癌症。目前治疗结肠癌的方法多种多样，但没有一种方法能根治结肠癌。在抗击这种致命疾病的斗争中，迫切需要新的药物靶点。目前的提案集中在一个这样的药物目标上。它是一种营养转运蛋白，被称为ATB0，由SLC6A14基因编码，负责运输所有必需的氨基酸和谷氨酰胺。这种转运蛋白只在正常组织中低水平表达，但在结肠癌中被诱导数倍。我们假设肿瘤细胞上调ATB0，+以满足它们对必需氨基酸和谷氨酰胺日益增长的需求。由于ATB0，+转运所有必需的氨基酸以及谷氨酰胺，足以让肿瘤细胞打开单个基因来满足它们的氨基酸需求。由于肿瘤细胞依赖ATB0，+作为必需氨基酸和谷氨酰胺的主要来源，阻断转运蛋白功能可能为癌症治疗提供一种合理的策略。为了验证这一战略，我们提出了三个具体目标。目的1在裸鼠移植瘤模型中评价基于shRNA的ATB0，+沉默对结肠癌细胞生长和进展的影响。在这里，我们将使用分子生物学方法使结肠癌细胞系中的转运蛋白沉默，然后检测当这些细胞被异种移植到裸鼠体内时，转运蛋白被击倒对肿瘤生长和进展的影响。目的2通过比较致癌物诱导肿瘤的形成和发展，评价ATB0，+缺失对结肠癌的影响。偶氮甲烷被用来诱导小鼠结肠癌。这是一种删除转运蛋白基因编码的遗传方法。我们预测，转运蛋白基因敲除的小鼠将对偶氮甲烷诱导的结肠癌产生抵抗力。目的3观察1-甲基-L-色氨酸(1-MLT)对两种不同的小鼠结肠癌模型：人结肠癌细胞系异种移植模型和致癌物诱导的小鼠结肠癌模型的药理阻断作用。这是一种阻断转运蛋白功能的药理学方法。我们将使用1-MLT作为ATB0，+的阻断剂来评估其在这些动物模型中预防结肠癌的能力。1-MLT也是吲哚胺双加氧酶(IDO)的有效抑制剂。已知抑制IDO可以增强免疫系统对肿瘤的活性。因此，我们预测1-MLT在体内将通过两种不同的机制发挥抗癌作用：通过阻断肿瘤特异的营养转运蛋白ATB0，+从而使肿瘤细胞饥饿必需的氨基酸，以及通过抑制IDO从而增强免疫系统对肿瘤的活性。这些研究将产生关于癌症特异性氨基酸转运体ATB0，+治疗结肠癌的治疗潜力的重要信息。 公共卫生相关性： 该项目的目标是评估一种癌症特异性氨基酸转运体SLC6A14或ATB0+在结肠癌治疗中的治疗潜力。研究将涉及使用人类结肠癌细胞系的异种小鼠模型和致癌物诱导的小鼠结肠癌模型。在这些模型中，将通过两种方法来评估转运蛋白作为治疗结肠癌药物靶点的潜力：一种是缺失ATB0，+的遗传学方法(SLC6a14-/-小鼠)，另一种是使用ATB0，+的化学阻滞剂的药理学方法。