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-1α Autocrine Loop, and Reduces Orthotopic Tumor Growth

Abstract

Purpose: Inhibitors of heat-shock protein 90 (Hsp90) may interfere with oncogenic signaling pathways, including Erk, Akt, and hypoxia-inducible factor-1a (HIF-1a). 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-IRh and directly impairing IGF-IR phosphorylation. Hypoxia-and IL-6^mediated activation of HIF-1a or STAT3/STAT5 were substantially inhibited by 17-AAG. Moreover, a novel IL-6/STAT3/HIF-1a autocrine loop was effectively disrupted by Hsp90 blockade. In vivo, 17-DMAG significantly reduced s.c. tumor growth and diminished STAT3 phosphorylation and IGF-IRh 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.

Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin

“…Inhibitory effects on other growth factor signals have also been implicated, for example, IGF-1R (Lang et al, 2007b) and Kit (Bauer et al, 2006). We found that the reduced proliferation and radiosensitising effects of Hsp90 inhibition in oesophageal cancer cell lines correlated with a decrease in growth factor-induced signalling.…”

Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer

“…Results showed that knockdown of PFKFB3 not only reversed the enhanced aerobic glycolysis but also inhibited tumor cell proliferation and migration. The potential mechanisms of how IL-6 upregulates PFKFB3 are that IL-6 increases the expression of HIF-1 and HIF-1 activates transcription of PFKFB3 (29). However, what is the concrete mechanism of how IL-6 exerts its tumor promoting effect by regulating the PFKFB3 in CRC is still under further consideration.…”

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

“…3, CAU-CAAACAAGAACUUCCUACACCA; UGGUGUAGGAA-GUUCUUGUUUGAUG) and Lipofectamine (Invitrogen; ref. 43). For experiments using stealth RNAi, sole administration of Lipofectamine to the culture medium served as a control.…”