Multiple kinase pathways involved in the different de novo sensitivity of pancreatic cancer cell lines to 17-AAG

Heping Liu, Ti Zhang, Rong Chen, David J. McConkey, John F. Ward, Steven A. Curley

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 17-Allylamino-17-demethoxygeldanamycin (17-AAG) specifically targets heat shock protein (HSP)90 and inhibits its chaperoning functions for multiple kinases involved in cancer cell growth and survival. To select responsive patients, the molecular mechanisms underlying the sensitivity of cancer cells to 17-AAG must be elucidated. Materials and Methods: We used cytotoxicity assays and Western blotting to explore the effects of 17-AAG and sorafenib on cell survival and expression of multiple kinases in the pancreatic cancer cell lines AsPC-1 and Panc-1. Gene cloning and transfection, siRNA silencing, and immunohistochemistry were used to evaluate the effects of mutant p53 protein on 17-AAG sensitivity. Results: AsPC-1 and Panc-1 responded differently to 17-AAG, with half maximal inhibitory concentration (IC 50) values of 0.12 and 3.18 μM, respectively. Comparable expression of HSP90, HSP70, and HSP27 was induced by 17-AAG in AsPC-1 and Panc-1 cells. P-glycoprotein and mutant p53 did not affect 17-AAG sensitivity in these cell lines. Multiple kinases are more sensitive to HSP90 inhibition in AsPC-1 than in Panc-1 cells. After 17-AAG treatment, p-Bad (S112) decreased in AsPC-1 cells and increased in Panc-1 cells. Sorafenib markedly increased p-Akt, p-ERK1/2, p-GSK-3β, and p-S6 in both cell lines. Accordingly, 17-AAG and sorafenib acted antagonistically in AsPC-1 and Panc-1 cells, except at high concentrations in AsPC-1 cells. Conclusions: Differential inhibition of multiple kinases is responsible for the different de novo sensitivity of AsPC-1 and Panc-1 cells to HSP90 inhibition. P-glycoprotein and mutant p53 protein did not play a role in the sensitivity of pancreatic cancer cells to 17-AAG.

Original languageEnglish (US)
Pages (from-to)147-153
Number of pages7
JournalJournal of Surgical Research
Volume176
Issue number1
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

Keywords

  • 17-AAG
  • chemosensitivity
  • kinase
  • pancreatic cancer

ASJC Scopus subject areas

  • Surgery

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