期刊
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
卷 82, 期 3, 页码 E563-E572出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ijrobp.2011.06.1999
关键词
Cisplatin resistance; Insulin-like growth factor binding protein-3; IGFBP-3; Lung cancer; Radiotherapy
资金
- National Cancer Institute [1R01 CA125842-01A1]
- Vanderbilt's Specialized Programs of Research Excellence in Lung Cancer [P50CA90949]
- Vanderbilt CTSA from the National Center for Research Resources [UL1 RR024975]
Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in nonesmall-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. (C) 2012 Elsevier Inc.
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