SERM Regulation of PAK Pathway in Endometrial Cancer

SERM 对子宫内膜癌 PAK 通路的调节

• 批准号: 6815054
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815054
• 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（由申请人提供）：子宫内膜癌是女性生殖道最常见的恶性肿瘤。现在可以接受的是，长期使用合成雌激素受体调节剂（SERM）（例如他莫昔芬）与患上子宫内膜癌的风险增加有关。除子宫内膜癌外，他莫昔芬的使用还与子宫内膜增厚，功能失调的子宫出血，子宫内膜息肉，子宫内膜增生和子宫肉瘤有关。尽管有关SERM临床实用性的信息显着增长，但了解Serm的细胞靶标调节子宫内膜癌变的机制的进展仍然难以捉摸。如下所述，我们最近的工作表明刺激P21激活的激酶（PAK1）是一种丝氨酸/苏氨酸信号激酶，在细胞运动，侵袭性和存活中起着重要作用，所有这些都需要肿瘤进展（7）。我们的初步研究发现，Serm刺激PAK1的表达和活性，Dynein Light链1（DLC1）是PAK1的生理靶标，并且PAK1-DLC1途径可能与子宫内乳腺癌的分子发病相关。在这里，我们建议研究在Serm暴露后，PAK1和DLC1参与子宫内膜癌细胞中雌激素受体功能（ER）功能和肿瘤表型的调节。 由于PAK1和DLC1的过度X级可能有助于侵袭性表型的发展，因此子宫内膜中PAK1途径的功能障碍可能构成子宫内膜癌发展的重要早期步骤。因此，我们的工作假设是“ PAKL活性的SERM介导的放松管制刺激DL C磷酸化和ER功能，因此有助于增强细胞的存活，锚定独立性，并有助于子宫内膜癌细胞的进展； PAKL的这些表型可以通过PAK1和其他PAK1的pak1降低。 相互作用”。此外，我们还将描绘出子宫内膜癌细胞中PAK1和DLC1的非ER非依赖性致瘤功能。为了解决这些假设，我们的具体目的是确定：（1）子宫内膜癌细胞中Serm调节PAK1的生化基础和功能意义； （2）DLC过表达和PAK1调节DLC1功能对与子宫内膜癌进展相关的表型变化的影响； （3）SERM对PTEN杂合小鼠进展模型的生物子宫内膜肿瘤发生对PAKL和DLC1功能的影响； （4）他在人类多步子子宫内膜癌发病机理中PAK1和DLC1的表达特征和意义。 我们建议的一个创新方面是使用新型体外，体内转基因模型和人类子宫内膜肿瘤，并具有后续数据，以获得有关PAK1和DLC1在子宫内膜癌生物学和肿瘤发生中的作用的新见解。这些研究将独特地定义DLC1及其上游PAK1激酶调节子宫内膜癌细胞的生存，有丝分裂和肿瘤发生的机制。我们提出的研究很重要，因为从这项研究中获得的知识将增强我们对新鉴定的Serm在子宫内膜生物学中新鉴定的细胞靶标的作用的理解。通过将PAK1-DLC识别为鉴定出新的分子靶标，检测和治疗子宫内膜癌的新进展，对关键调节途径的更好理解可能构成了新进展的基础，这是通过将PAK1-DLC鉴定为精华素作用中的关键调节信号传导结节。