Targeting filamin A reduces K-RAS–induced lung adenocarcinomas and endothelial response to tumor growth in mice
| Autor: | Jan Borén, Björn Redfors, Martin O. Bergo, Mohamed X. Ibrahim, Rajesh K. Nallapalli, Sashidar Bandaru, Yihai Cao, Yin Zhang, David Pazooki, Sai Naresh Sunkara, Levent M. Akyürek, Alex X. Zhou |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Cancer Research Cell signaling Lung Neoplasms Angiogenesis Fibrosarcoma Filamins Adenocarcinoma of Lung Biology Adenocarcinoma Filamin lcsh:RC254-282 Mice Contractile Proteins Cell Movement Teknik och teknologier Gene Order medicine FLNA Animals Protein kinase B Cytoskeleton Migration Cell Proliferation Cancer Mice Knockout Cell growth Research Myocardium Microfilament Proteins Gene targeting Endothelial Cells Fibroblasts lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Cell biology Tumor Burden Gene Expression Regulation Neoplastic Mice Inbred C57BL Genes ras Oncology Gene Targeting Cancer research Molecular Medicine Engineering and Technology Medicine Female |
| Zdroj: | Molecular Cancer Molecular Cancer, Vol 11, Iss 1, p 50 (2012) |
| DOI: | 10.7916/d8v40sk9 |
| Popis: | Background Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro. Methods First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. Results Knockout of Flna significantly reduced K-RAS–induced lung tumor formation and the proliferation of oncogenic K-RAS–expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. Conclusions We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics. |
| Databáze: | OpenAIRE |
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