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

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. (Tuberc Respir Dis 2007; 63: 42-51)

Prx1 modulates the chemosensitivity of lung cancer to docetaxel through suppression of FOXO1-induced apoptosis

“…Many studies have shown that Akt directly phosphorylates FOXO transcription factors (37)(38)(39) and the mechanisms through which Akt regulates FOXO transcription factors have been previously elucidated (40). Phosphorylation of FOXO by Akt triggers the rapid relocalization of FOXO proteins from the nucleus to the cytoplasm and results in the inhibition of FOXO-dependent transcription of its target genes, such as FasL and Trail (41)(42)(43)(44)(45). Because FOXO is intimately associated with the death-receptor mediated apoptotic pathway, we investigated the possibility that the FOXO family proteins may act as mediators of the increased apoptosis observed in shPrx1-infected A549 cells treated with docetaxel.…”

Elevated Prx1 Provides Resistance to Docetaxel, But Is Not Associated with Predictive Significance in Lung Cancer

“…Many studies have shown that Akt directly phosphorylates FOXO transcription factors33,34, and the mechanisms through which Akt regulates FOXO transcription factors have been previously elucidated35. Phosphorylation of FOXO by Akt triggers rapid relocalization of FOXO proteins from the nucleus to the cytoplasm leading to inhibition of FOXO-dependent transcription of its target genes such as FasL and TRAIL26,36,37. We have found that A549 xenograft tumors express FOXO1, but not other members of the FOXO family (data not shown).…”