Role of LMPTP in Prostate Cancer

摘要 这项建议的目的是对低分子量蛋白质进行探索性检查。 酪氨酸磷酸酶(LMPTP)作为前列腺癌治疗的新靶点。前列腺癌是 美国男性癌症死亡的主要原因，以及抑制前列腺癌生长和治疗的新疗法 转移是癌症中一个尚未得到满足的主要医疗需求。LMPTP是一种酪氨酸磷酸酶，由 ACP1基因。最近的一些报告表明，LMPTP在人类前列腺中过表达 LMPTP的表达与术后生化复发和病程缩短有关 生存时间。由于对LMPTP在肿瘤生长中的作用知之甚少，我们决定研究 LMPTP在前列腺癌细胞中的作用我们产生了携带LMPTP基因敲除的前列腺癌细胞系 (KO)，并发现LMPTP的缺失显著损害了它们的增殖、克隆形成和 体外侵袭性。我们还发现LMPTP是体内前列腺癌生长的关键促进剂。我们有 更多初步数据表明，LMPTP促进前列腺雄激素受体的激活 癌细胞。在这里，我们的目标是获得探索性证据，证明LMPTP作为一种新的靶点 前列腺癌治疗。我们试图确定LMPTP促进前列腺癌的分子机制 癌细胞生长(目标1)，并证明药物抑制LMPTP逆转去势- 抵抗前列腺癌生长并损害前列腺癌骨转移(目标2)。我们的项目是探索性的， 高风险，并对前列腺癌有明确的翻译前景。我们将使用Unique来执行此项目 我们已经开发的资源，包括一种新的患者来源的前列腺癌骨转移模型 以及一种新开发的具有良好药理特性的LMPTP抑制剂。我们独一无二 准备在这项研究中取得成功，并很高兴发现LMPTP作为一种新的目标的潜力 前列腺癌治疗。

ABSTRACT The objective of this proposal is to perform exploratory examination of the low molecular weight protein tyrosine phosphatase (LMPTP) as a new target for prostate cancer therapy. Prostate cancer is among the leading causes of cancer death in American men, and novel therapies to inhibit prostate tumor growth and metastasis are a major unmet medical need in cancer. LMPTP is a tyrosine phosphatase encoded by the ACP1 gene. Several recent reports have demonstrated that LMPTP is overexpressed in human prostate tumors, and that LMPTP expression associates with post-surgical biochemical recurrence and shorter patient survival time. Since little was known about the role of LMPTP in tumor growth, we decided to investigate the role of LMPTP in prostate cancer cells. We generated prostate cancer cell lines carrying LMPTP knockout (KO), and found that loss of LMPTP significantly impaired their proliferation, colony formation, and invasiveness in vitro. We also found that LMPTP is a key promoter of prostate tumor growth in vivo. We have additional preliminary data demonstrating that LMPTP promotes activation of the androgen receptor in prostate cancer cells. Here, our goal is to gain exploratory evidence of the potential for LMPTP as a novel target for prostate cancer therapy. We seek to determine the molecular mechanism by which LMPTP promotes prostate cancer cell growth (Aim 1) and to demonstrate that pharmacological LMPTP inhibition reverses castration- resistant prostate tumor growth and impairs prostate tumor bone metastasis (Aim 2). Our project is exploratory, high-risk, and has a clear translational perspective for prostate cancer. We will pursue this project using unique resources that we have developed, including a novel patient-derived bone metastasis model for prostate cancer and a newly developed LMPTP inhibitor with excellent pharmacological properties. We are uniquely positioned to succeed in this study and are excited to uncover the potential of LMPTP as a novel target for prostate cancer therapy.