AKT-Vimentin interaction; a potential role in soft tissue sarcoma progression and

AKT-波形蛋白相互作用；

• 批准号: 8249120
• 负责人: MENASHE BARELI
• 金额: $ 31万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249120
• 关键词: AKT inhibition; Accounting; Address; Adhesions; Affect; Aneuploidy; Apoptosis; Architecture; Attention; Automobile Driving; Back; Behavior; Binding; Carcinoma; Cell Cycle Arrest; Cell Line; Cell physiology; Cells; Chromosomal translocation; Clinical; Complex; Cytogenetics; Data; Disease; Distant; Environment; Epithelial; Etiology; Family; Goals; Growth; Heterogeneity; Histology; Human; Human Cell Line; Immigration; In Vitro; Induction of Apoptosis; Intermediate Filaments; Investigation; Karyotype; Knowledge; Laboratories; Learning; Lung; Malignant - descriptor; Malignant Fibrous Histiocytoma; Malignant Neoplasms; Mesenchymal; Modeling; Molecular; Molecular Profiling; Mus; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Preclinical Testing; Process; Property; Proto-Oncogene Proteins c-akt; Recurrence; Regulation; Research; Resistance; Role; Sampling; Secondary to; Signal Pathway; Signal Transduction; Structural Protein; Therapeutic; Tissues; Translating; Tumor Markers; Undifferentiated; Vimentin; Xenograft Model; Xenograft procedure; abstracting; base; cancer cell; cell motility; epithelial to mesenchymal transition; fibrosarcoma; improved; in vivo; interest; leiomyosarcoma; migration; mouse model; neoplastic cell; novel; novel therapeutic intervention; outcome forecast; pre-clinical; protein kinase C kinase; sarcoma; soft tissue; stem; treatment center; tumor; tumorigenic

Project Summary/Abstract Soft tissue sarcomas (STS) constitute a family of mesenchymal -origin malignancies that can occur anywhere in the body. Comprising more than 50 distinct histological subtypes, STS share several distinctive features that include frequent local recurrence after definitive therapy, marked chemoresistance, and frequent metastasis, especially to the lungs. These features translate to a dismal outcome, especially for those patients harboring high grade complex karyotype STS histologies, consisting mainly of leiomyosarcoma and high grade pleomorphic sarcoma ( malignant fibrous histiocytoma and fibrosarcoma). To improve STS therapeutic outcome it will be critical to develop novel agents that capitalize on underlying STS points of molecular vulnerability; however, progress towards this urgent goal are hampered by our minimal understanding of the molecular determinants underlying STS prog ression and dissemination. Tumor cells, including STS, respond to signaling cascades that control growth regulation processes and other components of the malignant process such as motility, invasion, induction of apoptosis, etc. Among theses signaling mechanisms, the AKT kinase pathway may be particularly important in STS growth and dissemination. Phosphorylation of AKT is a critical step in this cascade, had has been associated with impaired STS prognosis when identified in STS tissues. In human STS cell lines and human STS xenografts growing in immuno -incompetent mice, AKT inhibition interferes with STS growth, perhaps by disrupting AKT interaction with vimentin, a critical structural protein that may also have oncologically-relevant functional properties. Our group is apparently the first to identify the existence of AKT -vimentin interactions. We propose to study the regulation of this interaction, hoping to learn more about the mechanisms underlying these interactions, the functional significance of this interaction regarding how it impacts on STS proliferation and metastasis in vivo, and finally to test preclinical therapeutic approaches to AKT and vimentin blockade, hoping to demonstrate preclinical relevance using human STS xenograft mouse models and murine sarcoma models.

项目总结/文摘