gms | German Medical Science

27th German Cancer Congress Berlin 2006

German Cancer Society (Frankfurt/M.)

22. - 26.03.2006, Berlin

Blockade of heat-shock protein 90 (Hsp90) disrupts insulin-like growth factor-I receptor (IGF-IR) signaling in human pancreatic cancer cells and inhibits tumor cell migration in vitro

Meeting Abstract

  • corresponding author presenting/speaker Sven Arke Lang - Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Deutschland
  • Dagmar Klein - Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg
  • Hans Jürgen Schlitt - Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg
  • Edward Karl Geissler - Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg
  • Oliver Stöltzing - Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPO499

The electronic version of this article is the complete one and can be found online at:

Published: March 20, 2006

© 2006 Lang et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.



Introduction: The insulin-like growth factor-I receptor (IGF-IR) promotes angiogenesis and growth of human pancreatic cancer through up-regulating hypoxia-inducible factor-1a (HIF-1α) and vascular endothelial growth factor (VEGF). In addition, activation of IGF-IR may confer chemoresistance. Recently, specific inhibitors to heat-shock protein 90 (Hsp90) have been shown to interfere with multiple signaling pathways, including MAPK, PI-3K and HIF-1α, which are also involved in IGF-IR signaling cascades. We hypothesized that blocking Hsp90 in pancreatic cancer cells inhibits IGF-I mediated VEGF expression and cell motility, and subsequently improves chemosensitivity in vitro.

Methods: Human pancreatic cancer cells (HAPF-II, L3.6pl) were used for experiments. Effects of Hsp90 inhibition by 17-allylamino geldanamycin (17AAG) on IGF-I-mediated activation of IGF-IR and down-stream signaling substrates were investigated by Western blotting. In addition, HIF-1α was assessed by Western blotting and real-time PCR. IGF-I-induced cell migration and invasion were investigated in in vitro assays in the presence or absence of 17AAG. Sensitivity of tumor cells to chemotherapy (gemcitabine, oxaliplatin, 5-FU) +/- 17AAG, was evaluated in vitro (MTT assays). To elucidate the impact of Hsp90 inhibition on angiogenic factor expression, alterations in constitutive and inducible VEGF secretion were determined by ELISA and PCR.

Results: 17AAG not only abrogated activation of signaling intermediates such as MAPK/Erk, PI-3K/Akt, STAT3, and HIF-1α, blocking Hsp90 also directly inhibited the phosphorylation of IGF-IR and the down-stream substrate IRS-1. Interference with IGF-I signaling led to a significant reduction in constitutive and IGF-I-induced VEGF secretion. Furthermore, cancer cell motility and invasion were significantly inhibited (P<0.05).17AAG enhanced the antiproliferative effects of gemcitabine, 5-FU and oxaliplatin in vitro (P<0.05, for all).

Conclusions: Targeting Hsp90 function may be a valuable approach to improve the antiangiogenic/antineoplastic efficacy of conventional agents used for treating patients with pancreatic cancer.