Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells

Yunguang Sun, Siyuan Zheng, Artour Torossian, Christina K. Speirs, Stephen Schleicher, Nicholas J. Giacalone, David P. Carbone, Zhongming Zhao, Bo Lu

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis. Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor. Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation. Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

Original languageEnglish (US)
Pages (from-to)e563-e572
JournalInternational Journal of Radiation Oncology Biology Physics
Volume82
Issue number3
DOIs
StatePublished - Mar 1 2012

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Keywords

  • Cisplatin resistance
  • IGFBP-3
  • Insulin-like growth factor binding protein-3
  • Lung cancer
  • Radiotherapy

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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