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。目前公认，长期使用合成雌激素受体调节剂（SERM）如他莫昔芬与子宫内膜癌发生风险增加有关。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。尽管关于SERM临床应用的信息显著增长，但在理解SERM的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。如下文所述，我们最近的工作表明，p21激活激酶（Pak 1）（一种丝氨酸/苏氨酸信号传导激酶）的刺激在细胞运动性、侵袭性和存活中起着重要作用，所有这些都是肿瘤进展所需的（7）。我们的初步研究发现，SERM刺激Pak 1的表达和活性，动力蛋白轻链1（dynein light chain 1，DLC 1）是Pak 1的生理靶点，Pak 1-DLC 1通路可能参与子宫内膜癌的分子发病机制。在这里，我们建议调查Pak 1和DLC 1参与调节雌激素受体（ER）的功能和肿瘤发生表型在子宫内膜癌细胞SERM曝光后的分子机制。 由于Pak 1和DLC 1的过度表达可能导致侵袭性表型的发展，子宫内膜中Pak 1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“Pakl活性的SERM介导的失调刺激DL C磷酸化和ER功能，并因此有助于子宫内膜癌细胞的增强的细胞存活、锚定独立性和进展; Pakl的这些表型效应可能由Pakl的ER磷酸化控制，并通过Pakl调节DLC 1-ER相互作用进一步增强”。此外，我们还将描绘ER的Pak 1和DLC 1在子宫内膜癌细胞中的非依赖性致瘤功能。为了验证这些假说，我们的具体目标是确定：（1）子宫内膜癌细胞中SERM调节Pak 1的生化基础和功能意义;（2）DLC过表达和Pak 1调节DLC 1功能对子宫内膜癌进展相关表型变化的影响;（3）SERM对Pak 1和DLC 1功能的影响，以及对Pten杂合子小鼠子宫内膜肿瘤生物学发生的影响;（4）Pak 1和DLC 1在子宫内膜癌多阶段发病过程中的表达特点及意义。 我们的建议的一个创新方面是使用新的体外，体内转基因模型，和人类子宫内膜肿瘤的后续数据，以获得新的见解Pak 1和DLC 1在子宫内膜癌的生物学和肿瘤发生中的作用。这些研究将独特地定义DLC 1及其上游Pak 1激酶调节子宫内膜癌细胞存活、有丝分裂和肿瘤发生的机制。我们提出的研究是重要的，因为从这项研究中获得的知识将提高我们对新发现的SERM细胞靶点在子宫内膜生物学中的作用的理解。更好地了解在癌症进展中发挥作用的关键调控途径，可能会为确定新的分子靶点，检测和治疗子宫内膜癌的新进展奠定基础，方法是将Pak 1-DLC确定为SERM作用中的关键调控信号结节。