SERM Regulation of PAK Pathway in Endometrial Cancer

SERM 对子宫内膜癌 PAK 通路的调节

• 批准号: 6929343
• 负责人: RAKESH KUMAR
• 金额: $ 30.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929343
• 关键词: carcinogenesis; dynein ATPase; estrogen analog; estrogen inhibitor; estrogen receptors; female; genetically modified animals; hormone related neoplasm /cancer; human tissue; laboratory mouse; pharmacokinetics; protein protein interaction; protein structure function; serine threonine protein kinase; uterus neoplasms; women' s health

DESCRIPTION (provided by applicant): Endometrial cancer is the most common malignancy of the female genital tract. It is now accepted that the long-term use of synthetic estrogen receptor modulators (SERM) such as tamoxifen are associated with an increased risk of developing endometrial cancer. In addition to endometrial cancer, tamoxifen use has also been associated with endometrial thickening, dysfunctional uterine bleeding, endometrial polyps, endometrial hyperplasia, and uterine sarcoma. Despite the remarkable growth of information about the clinical utility of SERM, the progress in understanding the mechanism by which cellular target(s) of SERMs modulate endometrial carcinogenesis remains elusive. As described below, our recent work suggests that stimulation of p21-activated kinase (Pak1), a serine/threonine signaling kinase, plays a significant role in cell motility, invasiveness and survival, all of which are required for tumor progression (7). Our preliminary studies have discovered that SERM stimulates the expression and activity of Pak1, that dynein light chain 1 (DLC1) is a physiological target of Pak1, and that the Pak1-DLC1 pathway may be involved in the molecular pathogenesis of endometrial cancer. Here we propose to investigate the molecular mechanism by which Pak1 and DLC1 participate in the regulation of estrogen receptor (ER) functions and tumorigenic phenotypes in endometrial cancer cells upon SERM exposure. Since hyperexpression of Pak1 and DLC1 may contribute to the development of aggressive phenotypes, dysfunction in the Pak1 pathway in the endometrium may constitute an important early step(s) in endometrial cancer development. Thus, our working hypotheses are "SERM-mediated deregulation of Pakl activity stimulates DL C phosphorylation and ER functions, and consequently, contributes to an enhanced cell survival, anchorage-independence, and progression of endometrial cancer cells; these phenotypic effects of Pakl might be controlled by ER phosphorylation by Pak1 and further potentiated by Pak1 modulation of DLC1-ER interaction". In addition, we will also delineate ER-independent tumorigenic functions of Pak1 and DLC1 in endometrial cancer cells. To address these hypotheses, our specific aims are to determine: (1) The biochemical basis and functional significance of SERM regulation of Pak1 in endometrial cancer cells; (2) The influence of DLC overexpression and Pak1 regulation of DLC1 functions on the phenotypic changes associated with the progression of endometrial cancer; (3) The influence of SERM on the functions of Pakl and DLC1, and on the biology endometrial tumorigenesis using the Pten heterozygous mice progression model; and (4) he expression characteristics and significance of Pak1 and DLC1 during multi-step endometrial cancer pathogenesis in humans. An innovative aspect of our proposal is the use of novel in vitro, in vivo transgenic models, and human endometrial tumors with follow-up data to gain new insight about the roles of Pak1 and DLC1 in the biology and tumorigenesis of endometrial cancer. These studies will uniquely define the mechanisms through which DLC1 and its upstream Pak1 kinase regulate survival, mitogenesis and tumorigenesis of endometrial cancer cells. Our proposed research is significant in that the knowledge gained from this research will enhance our understanding of the roles of newly identified cellular targets of SERM in the biology of endometrium. A better understanding of critical regulatory pathways with roles in cancer progression is likely to form the basis for new advances in identifying novel molecular targets, detecting, and treating endometrial cancer, by identifying Pak1-DLC as key regulatory signaling nodule in the action of SERM.

描述(申请人提供)：子宫内膜癌是女性生殖道最常见的恶性肿瘤。现在公认的是，长期使用合成雌激素受体调节剂(SERM)，如他莫昔芬，与发生子宫内膜癌的风险增加有关。除了子宫内膜癌，他莫昔芬的使用还与子宫内膜增厚、功能失调性子宫出血、子宫内膜息肉、子宫内膜增生和子宫肉瘤有关。尽管有关SERM临床应用的信息显著增加，但SERM的细胞靶点(S)调控子宫内膜癌发生的机制仍不清楚。如下所述，我们最近的工作表明，刺激p21激活的激酶(PAC1)，一种丝氨酸/苏氨酸信号通路，在细胞的运动、侵袭和存活中发挥着重要作用，所有这些都是肿瘤进展所必需的。我们的初步研究发现，SERM可刺激Pak1的表达和活性，动力蛋白轻链1(DLC1)是Pak1的一个生理靶点，Pak1-DLC1通路可能参与了子宫内膜癌的分子发病机制。本研究旨在探讨Ak1和DLC1参与SERM对子宫内膜癌细胞雌激素受体(ER)功能和致瘤表型调控的分子机制。 由于Pak1和DLc1的高表达可能有助于侵袭性表型的发展，子宫内膜中Pak1通路的功能障碍可能是子宫内膜癌发生的重要早期步骤(S)。因此，我们的工作假设是“SERM介导的PACK活性的解除调节刺激了DLC的磷酸化和ER功能，从而有助于提高细胞的存活率、贴壁独立性和子宫内膜癌细胞的进展；这些表型效应可能由PAC1的ER磷酸化控制，并被PAC1对DLC1-ER相互作用的PAC1调节进一步增强”。此外，我们还将描述Pak1和DLC1在子宫内膜癌细胞中的ER非依赖性致瘤功能。为了解决这些假说，我们的具体目标是确定：(1)SERM调节Pak1在子宫内膜癌细胞中的生化基础和功能意义；(2)DLC过表达和DLC1功能调节对与子宫内膜癌进展相关的表型变化的影响；(3)SERM对Pak1和DLC1功能的影响，以及利用Pten杂合小鼠进展模型对子宫内膜肿瘤生物学发生的影响；以及(4)在人类子宫内膜癌多步骤发病过程中Pak1和DLC1的表达特点和意义。 我们建议的一个创新方面是使用新的体外和体内转基因模型，以及具有后续数据的人类子宫内膜肿瘤，以获得关于Ak1和DLC1在子宫内膜癌生物学和肿瘤发生中的作用的新见解。这些研究将独一无二地确定DLC1及其上游PK1激酶调控子宫内膜癌细胞存活、有丝分裂和肿瘤发生的机制。我们提出的研究具有重要意义，因为从这项研究中获得的知识将加强我们对新发现的SERM细胞靶点在子宫内膜生物学中的作用的理解。更好地了解关键调控通路在癌症进展中的作用，可能会通过识别Ak1-DLC作为SERM作用中的关键调控信号结节，为在识别新的分子靶点、检测和治疗子宫内膜癌方面取得新进展奠定基础。