IGF-I and IGF-II are potent mitogens, postulated to exert autocrine/paracrine effects on growth regulation in human lung cancer. Their proliferative effects are modulated by IGF-binding proteins (IGFBPs), which are found in conditioned medium (CM) of lung cancer cell lines. The biological role of the IGFBPs, which are ontogenetically and hormonally regulated, is not fully understood. Both inhibitory and stimulatory effects on cell growth have been demonstrated. Exogenous IGFBP-3 has been consistently shown to block IGF action, inhibiting cell growth in vitro. In order to evaluate the action of endogenously produced IGFBP-3 on cell growth in lung cancer, we stably transfected the non-small cell lung cancer cell line NCI-H23 with human IGFBP-3 cDNA (resulting in NCI-H23 pOPI3/BP-3) or with the vector pOPI3CAT as control (resulting in NCI-H23 pOPI3CAT). RT-PCR confirmed expression of IGFBP-3-specific mRNA in NCI-H23 pOPI3/BP-3, but not in N! CI-H23 or NCI-H23 pOPI3CAT. Western ligand blot and Western immunoblot analysis of CMs yielded strong signals of the characteristic 40-44 kDa human IGFBP-3 protein in NCI-H23 pOPI3/BP-3. An IGFBP-3 ELISA demonstrated a 20-fold increase in IGFBP-3 protein expression in NCI-H23 pOPI3/BP-3 as compared with NCI-H23. The growth of NCI-H23 pOPI3/BP-3 in serum-containing medium was significantly slower (1.7-fold) than that of NCI-H23 or the vector-transfected control NCI-H23 pOPI3CAT. While the proliferation rate of parental and vector-transfected cells could be stimulated by IGF-I, IGF-II, IGF-I analog Long R(3) IGF-I or insulin, that of NCI-H23 pOPI3/BP-3 could not. Xenotransplantation in nude mice resulted in marked tumor growth after the injection of NCI-H23 or NCI-H23 pOPI3CAT, but absent or minimal growth for the IGFBP-3-transfected cell line. These data suggest that IGFBP-3 is a potent inhibitor of cell growth in human lung cancer c! ell lines and may impair tumorigenicity in vivo.

This article has been cited by other articles:

				Y. Yin, J. Ni, M. Chen, Y. Guo, and S. Yeh RRR-{alpha}-Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects Clin. Cancer Res., January 1, 2009; 15(1): 190 - 200. [Abstract] [Full Text] [PDF]

				T. G. Harris, R. D. Burk, H. Yu, H. Minkoff, L. S. Massad, D. H. Watts, Y. Zhong, S. Gange, R. C. Kaplan, K. Anastos, et al. Insulin-Like Growth Factor Axis and Oncogenic Human Papillomavirus Natural History Cancer Epidemiol. Biomarkers Prev., January 1, 2008; 17(1): 245 - 248. [Abstract] [Full Text] [PDF]

				Y. Bosse, K. Maghni, and T. J. Hudson 1{alpha},25-Dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility, and remodeling processes Physiol Genomics, April 24, 2007; 29(2): 161 - 168. [Abstract] [Full Text] [PDF]

				N. Bhattacharyya, K. Pechhold, H. Shahjee, G. Zappala, C. Elbi, B. Raaka, M. Wiench, J. Hong, and M. M. Rechler Nonsecreted Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Can Induce Apoptosis in Human Prostate Cancer Cells by IGF-independent Mechanisms without Being Concentrated in the Nucleus J. Biol. Chem., August 25, 2006; 281(34): 24588 - 24601. [Abstract] [Full Text] [PDF]

				L. Jerome, N. Alami, S. Belanger, V. Page, Q. Yu, J. Paterson, L. Shiry, M. Pegram, and B. Leyland-Jones Recombinant Human Insulin-like Growth Factor Binding Protein 3 Inhibits Growth of Human Epidermal Growth Factor Receptor-2-Overexpressing Breast Tumors and Potentiates Herceptin Activity In vivo. Cancer Res., July 15, 2006; 66(14): 7245 - 7252. [Abstract] [Full Text] [PDF]

				C. E. Barbieri, C. A. Perez, K. N. Johnson, K. A. Ely, D. Billheimer, and J. A. Pietenpol IGFBP-3 Is a Direct Target of Transcriptional Regulation by {Delta}Np63{alpha} in Squamous Epithelium Cancer Res., March 15, 2005; 65(6): 2314 - 2320. [Abstract] [Full Text] [PDF]

				J. Pavelic, S. Krizanac, S. Kapitanovic, L. Pavelic, M. Samarzija, F. Pavicic, S. Spaventi, M. Jakopovic, Z. Herceg-Ivanovi, and K. Pavelic The Consequences of Insulin-Like Growth Factors/Receptors Dysfunction in Lung Cancer Am. J. Respir. Cell Mol. Biol., January 1, 2005; 32(1): 65 - 71. [Abstract] [Full Text] [PDF]

				A. C. Baege, G. L. Disbrow, and R. Schlegel IGFBP-3, a Marker of Cellular Senescence, Is Overexpressed in Human Papillomavirus-Immortalized Cervical Cells and Enhances IGF-1-Induced Mitogenesis J. Virol., June 1, 2004; 78(11): 5720 - 5727. [Abstract] [Full Text] [PDF]

				A. J. Butt, J. L. Martin, K. A. Dickson, F. McDougall, S. M. Firth, and R. C. Baxter Insulin-Like Growth Factor Binding Protein-3 Expression Is Associated with Growth Stimulation of T47D Human Breast Cancer Cells: The Role of Altered Epidermal Growth Factor Signaling J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1950 - 1956. [Abstract] [Full Text] [PDF]

				A. M. Mikheev, S. A. Mikheeva, B. Liu, P. Cohen, and H. Zarbl A functional genomics approach for the identification of putative tumor suppressor genes: Dickkopf-1 as suppressor of HeLa cell transformation Carcinogenesis, January 1, 2004; 25(1): 47 - 59. [Abstract] [Full Text] [PDF]

				K M Fong, Y Sekido, A F Gazdar, and J D Minna Lung cancer * 9: Molecular biology of lung cancer: clinical implications Thorax, October 1, 2003; 58(10): 892 - 900. [Abstract] [Full Text] [PDF]

				C. Liu, F. Lian, D. E. Smith, R. M. Russell, and X.-D. Wang Lycopene Supplementation Inhibits Lung Squamous Metaplasia and Induces Apoptosis via Up-Regulating Insulin-like Growth Factor-binding Protein 3 in Cigarette Smoke-exposed Ferrets Cancer Res., June 15, 2003; 63(12): 3138 - 3144. [Abstract] [Full Text] [PDF]

				S. M. Firth and R. C. Baxter Cellular Actions of the Insulin-Like Growth Factor Binding Proteins Endocr. Rev., December 1, 2002; 23(6): 824 - 854. [Abstract] [Full Text] [PDF]

				Y. S. Chang, L. Wang, D. Liu, L. Mao, W. K. Hong, F. R. Khuri, and H.-Y. Lee Correlation between Insulin-like Growth Factor-binding Protein-3 Promoter Methylation and Prognosis of Patients with Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., December 1, 2002; 8(12): 3669 - 3675. [Abstract] [Full Text] [PDF]

				Y. Kodama, R. C. Baxter, and J. L. Martin Insulin-Like Growth Factor-I Inhibits Cell Growth in the A549 Non-Small Lung Cancer Cell Line Am. J. Respir. Cell Mol. Biol., September 1, 2002; 27(3): 336 - 344. [Abstract] [Full Text] [PDF]

				H.-Y. Lee, K.-H. Chun, B. Liu, S. A. Wiehle, R. J. Cristiano, W. K. Hong, P. Cohen, and J. M. Kurie Insulin-like Growth Factor Binding Protein-3 Inhibits the Growth of Non-Small Cell Lung Cancer Cancer Res., June 1, 2002; 62(12): 3530 - 3537. [Abstract] [Full Text] [PDF]

				J. Hong, G. Zhang, F. Dong, and M. M. Rechler Insulin-like Growth Factor (IGF)-binding Protein-3 Mutants That Do Not Bind IGF-I or IGF-II Stimulate Apoptosis in Human Prostate Cancer Cells J. Biol. Chem., March 15, 2002; 277(12): 10489 - 10497. [Abstract] [Full Text] [PDF]

				M. Pold, M. Dohadwala, J. Luo, Y. Lin, and S. Dubinett Microarray Identifies Cyclo-oxygenase-2-Dependent Modulation of Insulin-like Growth Factor Binding Protein-3 in Non-small Cell Lung Cancer Cells Chest, March 1, 2002; 121(90030): 29S - 30S. [Full Text] [PDF]