Lang, Sven A. and Klein, Dagmar and Moser, Christian and Gaumann, Andreas and Glockzin, Gabriel and Dahlke, Marc H. and Dietmaier, Wolfgang and Bolder, Ulrich and Schlitt, Hans J. and Geissler, Edward K. and Stoeltzing, Oliver (2007) Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo. MOLECULAR CANCER THERAPEUTICS, 6 (3). pp. 1123-1132. ISSN 1535-7163,
Full text not available from this repository. (Request a copy)Abstract
Oncogenic signaling through activation of epidermal growth factor receptor (EGFR), HER-2, and hypoxia inducible-factor-1 alpha (HIF-1 alpha) has been implicated in gastric cancer growth and angiogenesis through upregulation of vascular endothelial growth factor (VEGF). Recently, heat shock protein 90 (Hsp90) has been identified as a critical regulator of oncogenic protein stability, including EGFR, HER-2, and HIF-1 alpha. We hypothesized that inhibition of Hsp90 impairs EGF- and hypoxiamediated angiogenic signaling in gastric cancer cells and consequently inhibits angiogenesis and tumor growth. In vitro, the geldanamycin derivate 17-allylamino-17-demethoxygeldanamycin (17-AAG) led to marked reduction in constitutive and inducible activation of extracellular signal-regulated kinase 1/2, Akt, and signal transducer and activator of transcription 3 and decreased nuclear HIF-1 alpha protein. In addition, EGFR and HER-2 were down-regulated after Hsp90 inhibition. With respect to regulation of angiogenic molecules, 17-AAG significantly reduced EGF-mediated VEGF secretion. Phosphorylation of focal adhesion kinase and paxillin were both abrogated by 17-AAG, which resulted in significant impairment of cancer cell motility. Interestingly, cytotoxic effects of 17-AAG in vitro were higher on cancer cells and gastric fibroblasts than on pericytes. In vivo, the water-soluble compound 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG; 25 mg/kg, thrice per week) significantly reduced s.c. xenografted tumor growth. By immunohistochemistry, 17-DMAG significantly reduced vessel area and numbers of proliferating tumor cells in sections. Furthermore, similar significant growth-inhibitory effects of 17-DMAG were achieved when administered as low-dose therapy (5 mg/kg, thrice per week). In conclusion, blocking Hsp90 disrupts multiple proangiogenic signaling pathways in gastric cancer cells and inhibits xenografted tumor growth in vivo. Hence, gastric cancer harbors attractive molecular targets for therapy with Hsp90 inhibitors, which could lead to improved efficacy of antineoplastic therapy regimens.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; RECEPTOR TYROSINE KINASE; SHOCK-PROTEIN 90; HSP90 INHIBITORS; BINDING PROTEIN; PHASE-I; ANGIOGENESIS; EXPRESSION; GELDANAMYCIN; OVEREXPRESSION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 21 Dec 2020 11:40 |
| Last Modified: | 21 Dec 2020 11:40 |
| URI: | https://pred.uni-regensburg.de/id/eprint/33138 |
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