Lang, Sven A. and Moser, Christian and Gaumann, Andreas and Klein, Dagmar and Glockzin, Gabriel and Popp, Felix C. and Dahlke, Marc H. and Piso, Pompiliu and Schlitt, Hans J. and Geissler, Edward K. and Stoeltzing, Oliver (2007) Targeting heat shock protein 90 in pancreatic cancer impairs insulin-like growth factor-I receptor signaling, disrupts an interleukin-6/signal-transducer and activator of transcription 3/hypoxia-inducible factor-1 alpha autocrine loop, and reduces orthotopic tumor growth. CLINICAL CANCER RESEARCH, 13 (21). pp. 6459-6468. ISSN 1078-0432,
Full text not available from this repository. (Request a copy)Abstract
Purpose: Inhibitors of heat-shock protein 90 (Hsp90) may interfere with oncogenic signaling pathways, including Erk, Akt, and hypoxia-inclucible factor-1 alpha (HIF-1 alpha). Because insulin-like growth factor-I receptor (IGF-IR) and signal transducer and activator of transcription 3 (STAT3) signaling pathways are implicated in the progression of pancreatic cancer, we hypothesized that blocking Hsp90 with geldanamycin derivates [17-allylamino-geldanamycin (17-AAG), 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG)] would impair IGF-I- and interleukin-6-mediated signaling and thus reduce pancreatic tumor growth and angiogenesis in vivo. Experimental Design: Human pancreatic cancer cells (HPAF-II, L3.6pl) were used for experiments. Changes in signaling pathway activation upon Hsp90 blockade were investigated by Western blotting. Effects of Hsp90 inhibition (17-AAG) on vascular endothelial growth factor were determined by ELISA and real-time PCR. Effects of 17-DMAG (25 mg/kg; thrice a week; i.p.) on tumor growth and vascularization were investigated in a s.c. xenograft model and in an orthotopic model of pancreatic cancer. Results: 17-AAG inhibited IGF-IR signaling by down-regulating IGF-IR beta and directly impairing IGF-IR phosphorylation. Hypoxia- and IL-6- mediated activation of HIF-1 alpha or STAT3/STAT5 were substantially inhibited by 17-AAG. Moreover, a novel IL- 6/STAT3/HIF-1 alpha autocrine loop was effectively disrupted by Hsp90 blockade. In vivo, 17-DMAG significantly reduced s.c. tumor growth and diminished STAT3 phosphorylation and IGF-IR beta expression in tumor tissues. In an orthotopic model, pancreatic tumor growth and vascularization were both significantly reduced upon Hsp90 inhibition, as reflected by final tumor weights and CD31 staining, respectively. Conclusions: Blocking Hsp90 disrupts IGF-I and IL-6- induced proangiogenic signaling cascades by targeting IGF-IR and STAT3 in pancreatic cancer, leading to significant growth-inhibitory effects. Therefore, we suggest that Hsp90 inhibitors could prove to be valuable in the treatment of pancreatic cancer.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; HSP90 INHIBITOR 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN; GASTRIC-CANCER; CELL-LINE; PROMOTER ACTIVITY; CARCINOMA CELLS; COLON-CANCER; NUDE-MICE; EXPRESSION; ANGIOGENESIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Nov 2020 07:43 |
| Last Modified: | 27 Nov 2020 07:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/31953 |
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