Tuberc Respir Dis.  2007 Jul;63(1):42-51. 10.4046/trd.2007.63.1.42.

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

• Lee YJ
• Park MY
• Kang YA
• Kwon SY
• Yoon HI
• Lee JH
• Lee CT

• KMID: 1877316
• DOI: http://doi.org/10.4046/trd.2007.63.1.42

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.

Keyword

TRAIL; Gefitinib; IGF-1R; Lung cancer

MeSH Terms

Adenoviridae
Animal Experimentation
Apoptosis
Cell Line*
Hand
Humans*
Lung Neoplasms*
Lung*
Protein-Tyrosine Kinases
RNA, Small Interfering
Protein-Tyrosine Kinases
RNA, Small Interfering

Figure

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  Figure 1 Changes of IGF-1R expression on the cell surface of lung cancer cell lines after transduction with ad-IGF-1R/482 and 950. (mean value of IGF-1R; Control: 20.6, ad-null: 18.7, ad-IGF-1R/482: 17.8, ad-IGF-1R/950: 138.5)

• 

  Figure 2 Suppression of IGF-1R expression by transduction with adenovirus-shIGF-1R

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  Figure 3 Enhancement of sensitivity of A549(resistant cell line to TRAIL) to TRAIL after transduction with ad-IGF-1R/482 and 950(p<0.01 compared with ad-null). No significant enhancement was found in NCI H460 (sensitive cell line to TRAIL). (Y-axis: relative survival)

• 

  Figure 4 Enhancement of sensitivity of A549(resistant cell line to TRAIL) to TRAIL after treatment with AG1024 (IGF-1R tyrosine kinase inhibitor). (p<0.05). (Y-axis: relative survival)

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  Figure 5 Enhancement of sensitivity of A549(resistant cell line to gefitinib) to gefitinib after transduction with ad-shIGF-1R. Significant enhancement was found at transduction with ad-shIGF-1R over 50 moi (p<0.05).(Y-axis: relative survival)

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  Figure 6 Blockade of dominant-acting genes such as IGF-1R using genetic and non-genetic inhibition (adopted from Lee CT and Carbone DP. Chapter 52 Gene Therapy in 'Lung Cancer' 3rd ed. Lippincott Williams & Wilkins with permission).

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