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Tumor Biology |
Departments of Thoracic/Head and Neck Medical Oncology [H-Y. L., K-H. C., W. K. H., J. M. K.] and Genitourinary Medical Oncology [S. A. W., R. J. C.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Department of Pediatrics, Mattell Children’s Hospital, University of California, Los Angeles, California 90095-1752 [B. L., P. C.]
Insulin-like growth factors (IGFs) have mitogenic and antiapoptotic properties and have been implicated in the development of lung cancer. The effects of IGFs are modulated by insulin-like growth factor binding proteins (IGFBPs). This study explored the effects of IGFBP-3 on non-small cell lung cancer (NSCLC) cells after infection with an adenovirus constitutively expressing IGFBP-3 under the control of the cytomegalovirus promoter (Ad5CMV-BP3). We found that IGFs, especially IGF-I, stimulated the growth of NSCLC cells, and Ad5CMV-BP3 suppressed this IGF-I-induced NSCLC cell growth. We also found that the clonogenicity of H1299 cells in soft agar was markedly reduced by Ad5CMV-BP3. Furthermore, direct injection of Ad5CMV-BP3 into H1299 NSCLC xenografts s.c. established in athymic nude mice induced massive destruction of the tumors. Ad5CMV-BP3 did not induce detectable cytotoxicity on normal human bronchial epithelial cells, suggesting therapeutic efficacy of this virus. Ad5CMV-BP3 infection was accompanied by apoptotic cell death in vitro as detected by flow cytometry, DNA fragmentation analysis, and Western blot analysis on the expression of Bcl-2 and on the cleavage of poly(ADP-ribose) polymerase, a substrate of caspase 3. Immunofluorescence confocal microscopy was also used to show the apoptotic effect of Ad5CMV-BP3 in H1299 tumors established in nude mice. These findings indicated that IGFBP-3 was a potent inducer of apoptosis in NSCLC cells in vitro and in vivo. To delineate the underlying mechanism, we examined the effect of IGFBP-3 on Akt/protein kinase B and glycogen synthase kinase-3ß, downstream mediators of the phosphatidylinositol 3-kinase pathway, and on mitogen-activated protein kinase (MAPK), all three of which are activated by IGF-mediated signaling pathways and have important roles in cell survival. IGFBP-3 overexpression inhibited the phosphorylation of Akt and glycogen synthase kinase-3ß and the activity of MAPK. Furthermore, IGF-I rescued the NSCLC cells from serum depletion-induced apoptosis, and this rescue was blocked in Ad5CMV-BP-3-infected H1299 NSCLC cells. Transient transfection with activated Akt or constitutively active MAPK kinase-1, an upstream activator of MAPK, partially blocked IGFBP-3-induced apoptosis of NSCLC cells. These findings suggested that the growth-regulatory effect of IGFBP-3 on NSCLC cells was attributable in part to the inhibition of the IGF-induced survival pathway. These data demonstrate the importance of IGFBP-3 in the regulation of NSCLC cell proliferation, clonogenicity, and tumor growth, suggesting that IGFBP-3 is a target for the treatment of lung cancer and that Ad5CMV-BP3 is a potential therapeutic agent.
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