"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: 8077946
• 负责人: VADIVEL GANAPATHY
• 金额: $ 15.51万
• 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/8077946
• 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; 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（由申请人提供）：结肠癌是该国第四大常见的癌症。目前使用多种策略来治疗结肠癌，但它们都无法永久治愈该疾病。迫切需要新的药物目标才能成功打击这种致命疾病。当前的提案重点是这样的药物目标。它是一种营养转运蛋白，称为ATB0，由基因SLC6A14编码，它运输所有必需的氨基酸和谷氨酰胺。该转运蛋白仅在正常组织中低水平表达，但在结肠癌中诱导了几倍。我们假设肿瘤细胞上调ATB0，以满足其对必需氨基酸和谷氨酰胺的需求不断增长。由于ATB0+运输所有必需的氨基酸以及谷氨酰胺，因此肿瘤细胞可以打开单个基因满足其氨基酸需求。由于肿瘤细胞依赖于ATB0，+是必需氨基酸和谷氨酰胺的主要来源，因此阻断转运蛋白功能可能会为癌症治疗提供逻辑策略。为了验证这一策略，我们提出了三个具体目标。目的1是评估ATB0的基于SHRNA的沉默，+对裸小鼠异种移植模型中结肠癌细胞系的肿瘤生长和进展的影响。在这里，我们将使用分子生物学方法在结肠癌细胞系中的转运蛋白沉默，然后检查转运蛋白敲低对这些细胞被异种移植到裸鼠中时肿瘤生长和进展的影响。 AIM 2是通过比较致癌物诱导的肿瘤的形成/进展来评估ATB0，+缺失对结肠癌的影响。甲氧甲烷用于诱导小鼠结肠癌。这是删除转运蛋白基因编码的遗传方法。我们预测，转运蛋白敲除小鼠将对甲氧基烷诱导的结肠癌具有抗性。目的3是在两种不同的结肠癌小鼠模型中，用1-甲基-L-色氨酸（1-MLT）评估ATB0的药理学阻断对肿瘤生长的影响：一种具有人类结肠癌细胞系和癌诱导的结肠癌癌小鼠小鼠模型的异种移植小鼠模型。这是阻止转运蛋白功能的药理方法。我们将使用1-MLT作为ATB0的阻滞剂，以评估其在这些动物模型中预防结肠癌的能力。 1-MLT也是吲哚胺二氧酶（IDO）的有效抑制剂。众所周知，IDO的抑制可以增强免疫系统对肿瘤的活性。因此，我们预测1-MLT通过通过两种不同的机制起作用来充当体内抗癌剂：通过阻断肿瘤特异性营养素转运蛋白ATB0，+饿死了必需氨基酸的肿瘤细胞，并通过抑制IDO，从而增强免疫系统的影响抗肿瘤。这些研究将产生有关癌症特异性氨基酸转运蛋白ATB0的治疗潜力的重要信息，用于治疗结肠癌。 公共卫生相关性： 该项目的目的是评估癌症特异性氨基酸转运蛋白（称为SLC6A14或ATB0）的治疗潜力，+在治疗结肠癌中。研究将涉及使用人类结肠癌细胞系的异种移植小鼠模型和致癌小鼠结肠癌的小鼠模型。在这些模型中，将评估转运蛋白作为治疗结肠癌的药物靶标的潜力：通过两种方法：通过删除ATB0，+（SLC6A14 - / - 小鼠）的遗传方法，并使用ATBB0，+的化学阻滞剂的药理学方法来评估。