Regulation of embryonic and stem cell differentiation by Ctr1 and cisplatin

Ctr1 和顺铂对胚胎和干细胞分化的调节

• 批准号: 8767743
• 负责人: DANIEL WEINSTEIN
• 金额: $ 7.7万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767743
• 关键词: Amphibia; Antibodies; Antineoplastic Agents; Biochemical; Biological Assay; Cause of Death; Cell Death; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Copper; Cytotoxic Chemotherapy; DNA; DNA Damage; Data; Effectiveness; Embryo; Embryonic Development; Etiology; Event; Fibroblast Growth Factor Receptors; Future; Germ Cell Cancers; Germ Cells; Germ Layers; Germ cell tumor; Human; Laboratories; Malignant Neoplasms; Mammalian Cell; Mediating; Mesoderm; Molecular; Mus; Pharmaceutical Preparations; Phenocopy; Platinum; Regulation; Relative (related person); Resistance; Signal Transduction; Signal Transduction Alteration; Signaling Molecule; Solid Neoplasm; Teratoma; Testing; Therapeutic Effect; United States; Xenopus; Xenopus laevis; base; cancer therapy; cell growth regulation; chemotherapeutic agent; crosslink; cytotoxic; embryonic stem cell; induced pluripotent stem cell; insight; loss of function; mouse model; prevent; public health relevance; research study; response; small molecule; stem; stem cell differentiation; success; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Cancer is the second leading cause of death in the United States. Despite remarkable advances in the use of small molecule- and antibody-based approaches to cancer treatment, many chemotherapeutic agents remain in widespread use decades after their discovery. The platinum-containing drug cisplatin is widely used for the treatment of solid tumors, and is particularly effective against germ cell tumors. Cisplatin exerts its cytotoxic effects through the formation of intrastrand crosslinks on DNA; the DNA damage triggers intracellular signaling networks that ultimately promote cell death. Cisplatin entry into cells is mediated by the transmembrane copper transporter Ctr1; to date, this molecule has not otherwise been thought to contribute to cisplatin's mechanism of action, nor has Ctr1 gain- or loss-of-function been implicated in oncogenesis or tumor progression. Our laboratory has demonstrated that Ctr1 additionally functions as a signaling molecule, and is required for mesoderm formation in the amphibian embryo as a component of the intracellular network downstream of the Fibroblast Growth Factor (FGF) receptor; furthermore, loss of Ctr1 inhibits the differentiation of mammalian embryonic stem (ES) cells. Surprisingly, we have found that cisplatin treatment phenocopies Ctr1 knockdown in amphibian differentiation assays, and induces precocious differentiation of mesoderm in human induced pluripotent stem (iPS) cells; these data suggest that cisplatin exerts its anticancer effects in germ cell tumors in part via regulation of cellular differentiation, possibly as a modulator of Ctr1 signaling. Experiments proposed in this application will determine whether the therapeutic effects of cisplatin are mediated in part by alteration of signal flow through Ctr1. We will identify the mechanisms underlying cisplatin-mediated regulation of differentiation in amphibian and mammalian cells. These studies should provide important insights into the potential treatment of germ cell and other solid tumors, and will test the hypothesis that Ctr1 is an important target for future chemotherapy regimens.

描述（由申请人提供）：癌症是美国第二大死亡原因。尽管在使用基于小分子和抗体的癌症治疗方法方面取得了显着进步，但在发现后数十年中，许多化学治疗剂仍在广泛使用中。含铂的药物顺铂被广泛用于治疗实体瘤，对生殖细胞肿瘤特别有效。顺铂施加 通过形成astrand内链接在DNA上的交联，其细胞毒性作用； DNA损伤会触发最终促进细胞死亡的细胞内信号传导网络。顺铂进入细胞是由跨膜铜转运蛋白CTR1介导的。迄今为止，否则尚未认为该分子有助于顺铂的作用机理，也没有与CTR1的增益或功能丧失有关，与肿瘤发生或肿瘤进展有关。我们的实验室表明，CTR1还作为信号分子起作用，并且是在两栖胚胎中形成中胚层所必需的，作为成纤维细胞生长因子（FGF）受体下游细胞内网络的组成部分。此外，CTR1的丢失抑制了哺乳动物胚胎干（ES）细胞的分化。令人惊讶的是，我们发现在两栖分化测定中敲除ctr1敲低的顺铂治疗，并在人类诱导的多能茎（IPS）细胞中诱导中胚层的早熟分化。这些数据表明，顺铂蛋白在细胞分化的一部分可能作为CTR1信号传导的调节剂来部分调节生殖细胞肿瘤中的抗癌作用。本应用程序中提出的实验将确定顺铂的治疗作用是否是通过CTR1信号流动改变的部分介导的。我们将确定两栖细胞和哺乳动物细胞中分化的调节的基础机制。这些研究应提供有关生殖细胞和其他实体瘤的潜在治疗方法的重要见解，并将检验以下假设：CTR1是未来化疗方案的重要靶标。