Enhancement of Sensitivity of Human Lung Cancer Cell Line to TRAIL and Gefitinib by IGF-1R Blockade.

Lee, Yoon Jin; Park, Mi Young; Kang, Young Ae; Kwon, Sung Youn; Yoon, Ho Il; Lee, Jae Ho; Lee, Choon Taek

doi:2007.63.1.42

Tuberc Respir Dis > Volume 63(1); 2007 > Article

Original Article

Tuberculosis and Respiratory Diseases 2007;63(1):42-51.
DOI: https://doi.org/10.4046/trd.2007.63.1.42 Published online July 1, 2007.

Enhancement of Sensitivity of Human Lung Cancer Cell Line to TRAIL and Gefitinib by IGF-1R Blockade.

Yoon Jin Lee, Mi Young Park, Young Ae Kang, Sung Youn Kwon, Ho Il Yoon, Jae Ho Lee, Choon Taek Lee

¹Department of Internal Medicine, Lung Institute of Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.
²Department of Medicine, Respiratory Center, Seoul National University Bundang Hospital, Seongnam, Korea. ctlee@snu.ac.kr

Abstract

BACKGROUND
TRAIL is a cytokine that selectively induces apoptosis in various cancer cell lines. Gefitinib is new targeted drug applied in lung cancer that selectively inhibits EGFR tyrosine kinase. However, lung cancers have shown an initial or acquired resistance to these drugs. This study examined the effect of IGF-1R and its blockade on enhancing the sensitivity of lung cancer cell lines to TRAIL and gefitinib. METHODS: Two lung cancer cell lines were used in this study. NCI H460 is very sensitive to TRAIL and gefitinib. On the other hand, A549 shows moderate resistance to TRAIL and gefitinib. The IGF-1R blockade was performed using adenoviruses expressing the dominant negative IGF-1R and shRNA to IGF-1R and AG1024 (IGF-1R tyrosine kinase inhibitor). RESULTS: The adenovirus expressing dominant negative IGF-1R(950st) induced the increased expression of defective IGF-1R on the lung cancer cell surface, and the adenovirus-shIGF-1R effectively decreased the level of IGF-1R expression on cell surface. The genetic blockade of IGF-1R by the adenovirus-dnIGF-1R and AG1024 increased the sensitivity of A549 cells to TRAIL. The reduction of IGF-1R by transduction with ad-shIGF-1R also increased the sensitivity of the A549 cells to gefitinib. CONCLUSION: The blockade of IGF-1R through various mechanisms increased the sensitivity of the lung cancer cell line that was resistant to TRAIL and gefitinib. However, further studies using other cell lines showing acquired resistance as well as in vivo animal experiments will be needed.

Key Words: TRAIL, Gefitinib, IGF-1R, Lung cancer