Suppression of Prostate Tumor Growth and Metastasis by Inhibition of Vimentin

通过抑制波形蛋白来抑制前列腺肿瘤的生长和转移

• 批准号: 9288139
• 负责人: Vivek M Rangnekar
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288139
• 关键词: Apoptosis; Apoptotic; Binding; Biological; Biology; Cancer Etiology; Cell Culture Techniques; Cell Surface Receptors; Cells; Cessation of life; Chemicals; Conditioned Culture Media; Development; Epithelial; Epithelial Cells; Family; Fibroblasts; GRP78 gene; Growth; Human; Hydrophobicity; Impaired wound healing; Knockout Mice; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mesenchymal; Metastatic Neoplasm to the Lung; Modeling; Molecular Target; Mus; Neoplasm Metastasis; Normal Cell; Organ; PAWR protein; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Primary Neoplasm; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Proteins; Quinolones; Resectable; Resistance; Role; Structure-Activity Relationship; Surface; Testing; Therapeutic; Tissues; Toxic effect; Tumor Suppressor Proteins; Vimentin; analog; androgen deprivation therapy; bone; cancer cell; cell motility; conventional therapy; extracellular; in vivo; insight; killings; member; men; metastatic process; mouse model; nanomolar; novel; paracrine; prostate cancer cell; prostate cancer model; public health relevance; quinoline; receptor; response; screening; small molecule; therapy resistant; tumor; tumor growth; tumor xenograft

 DESCRIPTION (provided by applicant): Advanced prostate tumors that often metastasize to the lung, bone, and other vital tissues, are resistant to conventional therapy. Prostate apoptosis response-4 (Par-4) is a tumor suppressor that causes apoptosis in therapy-resistant prostate cancer cells. Although baseline levels of Par-4 secreted by cells are inadequate to induce apoptosis, normal cells can be induced to produce robust secretion of Par-4 protein that targets cancer cells in a paracrine manner. Accordingly, secreted Par-4 is systemically available in vivo and binds to its cell surface receptor GRP78 in cancer cells to trigger apoptosis in primary and metastatic tumors. Importantly, secreted Par-4 induces cancer-specific apoptosis, but it does not induce apoptosis in normal cells as GRP78 is expressed only on the surface of cancer cells, not on normal cells. "Small-molecule" drugs that efficiently and selectively induce Par-4 secretion without killing the normal cells would, therefore, represent an important therapeutic advance. In preliminary studies, we synthesized and screened newly developed 3-arylquinolines as well as related quinolones and quinothiolones for the secretion of Par-4 protein from normal mouse and human fibroblast and epithelial cells. This screening led to the identification of 2-amino-7-(N,N-dimethylamino)-3-(2'-fluorophenyl)quinoline (called "Arylquin-1") as a member of a new class of agents that trigger robust secretion of Par-4 from normal cells at nanomolar, non-toxic concentrations. As expected, Par-4 secreted from these normal cells induced paracrine apoptosis in diverse prostate and lung cancer cell cultures, but not in normal cell cultures. Using a biotinylated, biologically active version of Arylquin-1, we identified vimentin, a protein linkedto motility, invasion, EMT and metastasis, as the molecular target of Arylquin-1 that in turn produces Par-4 secretion. In this study, we will determine the effect of Arylquin-1 on Par-4 secretion from normal cells and apoptosis in prostate cancer cell culture and in vivo, on tumor growth in prostate cancer models. Computational dynamics revealed that Arylquin-1 forms a stable interaction with a hydrophobic pocket on vimentin. We will, therefore, determine the domains of Par-4 and vimentin that bind to each other to elucidate the mechanism underlying inhibition of Par-4 secretion by vimentin and its release by Arylquin-1. Consistent with the interaction of Arylquin-1 with vimentin, our preliminary studies also indicated that Arylquin-1 inhibits motility and invasion in prostate cancer cells by an apoptosis-independent mechanism. We will, therefore, study whether Arylquin-1 inhibits motility, invasion and EMT in cell culture and metastasis in mouse models of prostate cancer via vimentin-dependent mechanisms. Developing agents that selectively promote Par-4 secretion from normal cells, induce apoptosis in cancer cells and halt metastatic processes in prostate cancer would be of extraordinary academic and therapeutic value.

 描述（由申请人提供）：经常转移至肺、骨和其他重要组织的晚期前列腺肿瘤对常规疗法具有抵抗力。前列腺细胞凋亡反应 4 (Par-4) 是一种肿瘤抑制因子，可在治疗中引起细胞凋亡。尽管细胞分泌的 Par-4 的基线水平不足以诱导细胞凋亡，但可以诱导正常细胞产生以旁分泌方式靶向癌细胞的 Par-4 蛋白的强烈分泌。是体内可全身利用，并与其在癌细胞中的细胞表面受体 GRP78 结合，引发原发性和转移性肿瘤的细胞凋亡。重要的是，分泌的 Par-4 诱导癌症特异性细胞凋亡，但它不会诱导正常细胞凋亡，因为 GRP78 仅表达。因此，我们在初步研究中合成并筛选了能够有效且选择性地诱导 Par-4 分泌而不杀死正常细胞的“小分子”药物。新开发的 3-芳基喹啉以及相关的喹诺酮类和喹硫酮类用于正常小鼠和人成纤维细胞和上皮细胞分泌 Par-4 蛋白。此次筛选鉴定出 2-氨基-7-(N,N-二甲基氨基)。 -3-(2'-氟苯基)喹啉（称为“Arylquin-1”）是触发 Par-4 强劲分泌的新型药物的一员正如预期的那样，这些正常细胞分泌的 Par-4 在不同的前列腺和肺癌细胞培养物中诱导旁分泌细胞凋亡，但在正常细胞培养物中则不然。 作为 Arylquin-1 的生物素化、生物活性版本，我们鉴定出波形蛋白（一种与运动、侵袭、EMT 和转移相关的蛋白质）作为 Arylquin-1 的分子靶标，进而产生 Par-4 分泌。在本研究中，我们将确定。 Arylquin-1 对正常细胞分泌 Par-4 以及前列腺癌细胞培养物和体内细胞凋亡的影响，以及对前列腺癌模型中肿瘤生长的影响计算动力学表明，Arylquin-1 形成稳定的相互作用。因此，我们将确定 Par-4 和波形蛋白相互结合的结构域，以阐明波形蛋白抑制 Par-4 分泌和 Arylquin-1 释放的潜在机制。由于 Arylquin-1 与波形蛋白的相互作用，我们的初步研究还表明，Arylquin-1 通过一种不依赖于细胞凋亡的机制抑制前列腺癌细胞的运动和侵袭。 Arylquin-1 通过波形蛋白依赖性机制抑制前列腺癌小鼠模型中的细胞培养物和转移中的运动、侵袭和 EMT，开发选择性促进正常细胞分泌 Par-4、诱导癌细胞凋亡并阻止前列腺转移过程的药物。癌症将具有非凡的学术和治疗价值。