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Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells. Int J Radiat Oncol Biol Phys 2012 Mar 01;82(3):e563-72

Date

12/27/2011

Pubmed ID

22197230

Pubmed Central ID

PMC3271860

DOI

10.1016/j.ijrobp.2011.06.1999

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.

Author List

Sun Y, Zheng S, Torossian A, Speirs CK, Schleicher S, Giacalone NJ, Carbone DP, Zhao Z, Lu B

Author

Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

AC133 Antigen
Aldehyde Dehydrogenase
Animals
Antigens, CD
Apoptosis
Biomarkers, Tumor
Blotting, Western
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Cell Survival
Chemoradiotherapy
Cisplatin
Drug Resistance, Neoplasm
Female
Glycoproteins
Humans
Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor I
Lung Neoplasms
Mice
Mice, Nude
Microarray Analysis
Peptides
RNA, Small Interfering
Radiation Tolerance
Radiation-Sensitizing Agents
Receptor, IGF Type 1
Recombinant Proteins
Signal Transduction
Xenograft Model Antitumor Assays
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a