SERM Regulation of PAK Pathway in Endometrial Cancer

SERM 对子宫内膜癌 PAK 通路的调节

• 批准号: 7228266
• 负责人: RAKESH KUMAR
• 金额: $ 29.35万
• 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/7228266
• 关键词: Address; Biochemical; Biology; Cancer Patient; Carcinoma; Cell Survival; Characteristics; Clinical; Data; Development; Endometrial; Endometrial Carcinoma; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Estrogen Receptor 1; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Female; Functional disorder; Genital system; Growth; Human; In Vitro; Knowledge; Laboratories; Lead; Ligands; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Target; Mus; N(delta)-acetylornithine, -isomer; N-dodecanoylglutamic acid, -isomer, sodium salt; Nodule; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Protein Overexpression; Purpose; Receptor Signaling; Regulation; Regulatory Pathway; Research; Risk; Role; Selective Estrogen Receptor Modulators; Serine; Signal Transduction; Stimulation of Cell Proliferation; Tamoxifen; Threonine; Transactivation; Transgenic Model; Up-Regulation; Uterine Corpus Sarcoma; Uterine Polyp; Uterine hemorrhage; Work; alpha-difluoromethyl-DOPA, -isomer; alpha-methylornithine dihydrochloride, -isomer; base; cancer cell; carcinogenesis; cell motility; cellular targeting; design; dynein light chain; follow-up; human RIPK1 protein; in vivo; innovation; insight; malignant breast neoplasm; mouse model; novel; p21 activated kinase; receptor function; tumor progression; tumorigenesis; tumorigenic; xenoestrogen

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。现在人们普遍认为，长期使用合成雌激素受体调节剂（SERM）如他莫昔芬会增加患子宫内膜癌的风险。除了子宫内膜癌之外，他莫昔芬的使用还与子宫内膜增厚、功能性子宫出血、子宫内膜息肉、子宫内膜增生和子宫肉瘤有关。尽管有关 SERM 临床用途的信息显着增长，但在理解 SERM 细胞靶点调节子宫内膜癌发生的机制方面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 激活激酶 (Pak1)（一种丝氨酸/苏氨酸信号激酶）在细胞运动、侵袭性和存活中发挥重要作用，所有这些都是肿瘤进展所必需的 (7)。我们的前期研究发现SERM刺激Pak1的表达和活性，动力蛋白轻链1（DLC1）是Pak1的生理靶点，Pak1-DLC1通路可能参与子宫内膜癌的分子发病机制。在这里，我们建议研究 Pak1 和 DLC1 参与 SERM 暴露后子宫内膜癌细胞雌激素受体 (ER) 功能和致瘤表型调节的分子机制。 由于 Pak1 和 DLC1 的过度表达可能有助于侵袭性表型的发展，因此子宫内膜中 Pak1 通路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“SERM 介导的 Pakl 活性失调会刺激 DL C 磷酸化和 ER 功能，因此有助于增强细胞存活、锚定独立性和子宫内膜癌细胞的进展；Pakl 的这些表型效应可能是由 Pak1 的 ER 磷酸化控制，并通过 Pak1 对 DLC1-ER 相互作用的调节进一步增强”。此外，我们还将描述 Pak1 和 DLC1 在子宫内膜癌细胞中的不依赖于 ER 的致瘤功能。为了解决这些假设，我们的具体目标是确定：（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对DLC1功能的调节对子宫内膜癌进展相关表型变化的影响； (3)利用Pten杂合子小鼠进展模型研究SERM对Pakl和DLC1功能以及子宫内膜肿瘤生物学发生的影响； (4)Pak1和DLC1在人类子宫内膜癌多步发病过程中的表达特征及意义。 我们提案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以及后续数据来获得有关 Pak1 和 DLC1 在子宫内膜癌的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增强我们对新发现的 SERM 细胞靶标在子宫内膜生物学中的作用的理解。通过将 Pak1-DLC 确定为 SERM 作用中的关键调控信号结节，更好地了解在癌症进展中发挥作用的关键调控途径可能为识别新分子靶点、检测和治疗子宫内膜癌的新进展奠定基础。