IGF-I and IGFBP-3 augment transforming growth factor-beta actions in human renal carcinoma cells.
Renal cell carcinoma (RCC) is the most prevalent cancer of the kidney. In human RCC cells, we recently showed that insulin-like growth factor I (IGF-I) has growth-promoting effects regulated by IGF-binding protein 3 (IGFBP-3). In this study, the analysis was expanded to include the interaction between the IGF and transforming growth factor-beta (TGF-beta) systems in the human RCC cells Caki-2 (from a primary tumor) and SK-RC-52 (from a metastasis). Functional effects such as cell proliferation, TGF-beta receptor (TbetaR) signaling, and IGFBP-3 levels were monitored after stimulation with various concentrations of IGF-I, TGF-beta, and IGFBP-3. In addition, human RCC tissues as well as experimental human RCC tumors were analyzed for cellular expression of phosphorylated Smad2 by immunohistochemistry. TGF-beta regulated the endogenous IGFBP-3 levels in these RCC cells as neutralizing anti-TGF-beta(1-3) antibodies strongly reduced the basal IGFBP-3 level. In addition, IGF-I increased the IGFBP-3 levels five- to eightfold with TGF-beta acting in synergy to enhance the IGFBP-3 levels 12- to 17-fold. Neutralizing TGF-beta(1-3) activity circumvented the growth inhibitory effects of IGFBP-3 seen in SK-RC-52, whereas it inhibited the growth-promoting effects of IGFBP-3 in Caki-2. Moreover, IGF-I interacted directly with TGF-beta activation of the TbetaR complex by enhancing phosphorylation and nuclear translocation of Smad2. This study demonstrates a direct interaction of the IGF and TGF-beta systems in human renal carcinoma cells. The observations that IGF-I enhances the TGF-beta signaling and that TGF-beta promotes IGFBP-3 production and thus influence the biological activity of IGF may be of importance for future therapeutic options.
Rosendahl
A H
AH
Department of Oncology, Institution of Clinical Sciences, Lund University, University Hospital, Lund, Sweden.
Forsberg
G
G
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020239:Receptor Cross-Talk / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D018972:Insulin-Like Growth Factor Binding Protein 3; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I