Validation of Galectin-3 as a Target in Cancer Therapy

Galectin-3 作为癌症治疗靶点的验证

• 批准号: 6572632
• 负责人: FU-TONG LIU
• 金额: $ 14.84万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-08 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6572632
• 关键词: apoptosis; bacterial virus; biotechnology; cell adhesion; cell line; cell proliferation; drug discovery /isolation; extracellular matrix proteins; galactosides; gene expression; gene induction /repression; genetic library; hepatocellular carcinoma; lectin; messenger RNA; molecular biology; neoplasm /cancer invasiveness; neoplasm /cancer therapy; nucleic acid hybridization; oligonucleotides; peptides; tissue /cell culture

DESCRIPTION (provided by applicant): Galectins are a recently recognized family of evolutionarily conserved -galactoside-binding animal lectins. Family members are involved in immunomodulation, induction and inhibition of cell death, cell cycle control, cell adhesion and association with tumors. Current trends indicate that galectins will serve as important diagnostic agents, prognostic indicators and therapeutic agents for a variety of neoplastic diseases. We have identified galectin-3 as a potential molecular target of intervention in several tumor types. The protein is upregulated in thyroid carcinoma, hapatocellular carcinoma, and certain types of lymphomas: normal thyroid epithelial cells, hepatocytes, and lymphocytes do not express galectin-3, but the corresponding cancerous tissue express the protein highly. We have demonstrated galectin-3's involvement in promoting proliferation of a leukemic tumor cell line under suboptimal growth conditions, and in inhibition of apoptosis. Many chemotherapeutic agents function by induction of apoptosis, and galectin-3 may reasonably be expected to contribute to therapeutic resistance by virtue of its function in the regulation of apoptosis. Recent high throughput screening data suggest that chemosensitivity of tumor cells is inversely related to the levels of galectin-3 expressed. Galectin-3 has also been shown to play a role in homotypic cell adhesion and adhesion of cells to extracellular matrix proteins. In addition, by transfection experiments, other investigators have related galectin-3 expression to the metastatic property of cancer cells. Thus, inhibitors of galectin-3 may be useful for treatment of cancers and our application seeks to validate galectin-3 as a potential therapeutic target with the following Specific Aims: 1. Development of inhibitors of galectin-3 expression. Galectin-3-specific antisense oligodeoxynucleotides will be generated and used to inhibit the expression of galectin-3 protein in cells. The effect of these inhibitors on cell growth and apoptosis of hepatocellular carcinoma cells will be evaluated. 2. Development of inhibitors of galectin-3 function. Oligonucleotide ligands (aptamers) for galectin-3 capable of selectively neutralizing galectin-3 function will be selected. Peptide inhibitors of galectin-3 will also be identified by the phage display technology. The effect of these inhibitors on adhesion of cancer cells to extracellular matrix proteins and invasive properties of cancer cells will be evaluated.

描述（由申请人提供）： 甲染蛋白是最近公认的进化保守的家族 - 半乳糖苷结合动物凝集素。 家庭成员参与 免疫调节，诱导和抑制细胞死亡，细胞周期控制， 细胞粘附和与肿瘤的关联。 当前趋势表明 甲状腺素将作为重要的诊断剂，预后指标和 各种肿瘤疾病的治疗剂。 我们已经确定Galectin-3是干预的潜在分子靶标 在几种肿瘤类型中。 该蛋白在甲状腺癌中上调， HAPATOCOLULUR癌和某些类型的淋巴瘤：正常甲状腺 上皮细胞，肝细胞和淋巴细胞不表达半乳糖素3，而是 相应的癌组织高度表达蛋白质。 我们有 证明了乳糖素3参与促进白血病的扩散 在次优的生长条件下肿瘤细胞系，并抑制 凋亡。 许多化学治疗剂通过诱导凋亡而起作用， Galectin-3可能会合理地预期有助于治疗 由于其在调节细胞凋亡中的功能而抗性。 最近的 高吞吐量筛查数据表明肿瘤细胞的化学强度为 与表达的Galectin-3的水平成反比。 Galectin-3也有 被证明在同型细胞粘附和细胞粘附中起作用 细胞外基质蛋白。 另外，通过转染实验， 其他研究人员将Galectin-3表达与转移性相关 癌细胞的特性。 因此，Galectin-3的抑制剂可能对 癌症的治疗和我们的应用程序旨在验证Galectin-3作为一个 潜在的治疗靶标具有以下特定目的： 1。乳肠蛋白3表达抑制剂的发展。 galectin-3特异性 反义寡脱氧核苷酸将产生并用于抑制 细胞中半乳糖素-3蛋白的表达。 这些抑制剂对 将评估肝细胞癌细胞的细胞生长和凋亡。 2。乳肠蛋白3功能的抑制剂的发展。 寡核苷酸配体 （适体）对于能够选择性中和lectectin-3的Galectin-3 将选择功能。 Galectin-3的肽抑制剂也将是 通过噬菌体显示技术确定。 这些抑制剂的效果 癌细胞粘附在细胞外基质蛋白上和侵入性 将评估癌细胞的特性。