Insulin-Like Growth Factor II Mediates Epidermal Growth Factor-Induced Mitogenesis in Cervical Cancer Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 1995-12, Vol.92 (26), p.11970-11974
• Main Authors: Steller, M A, Delgado, C H, Zou, Z
• Format: Article
• Language: English
• Subjects: Base Sequence; Cell culture techniques; Cell cycle; Cell growth; Cell lines; Cells; Cellular biology; Cervical cancer; Dose-Response Relationship, Drug; Epidermal Growth Factor - pharmacology; Female; Fibroblasts; Gene Expression - drug effects; Humans; Insulin-Like Growth Factor Binding Protein 5 - pharmacology; Insulin-Like Growth Factor I - biosynthesis; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor II - biosynthesis; Insulin-Like Growth Factor II - pharmacology; Kinetics; Medical research; Messenger RNA; Mitosis - drug effects; Molecular Sequence Data; Oligodeoxyribonucleotides - pharmacology; Oligonucleotides, Antisense - pharmacology; Receptor, IGF Type 1 - metabolism; Receptors; RNA; RNA, Messenger - metabolism; Tumor Cells, Cultured; Uterine Cervical Neoplasms - pathology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.26.11970

There is increasing evidence that activation of the insulin-like growth factor I (IGF-I) receptor plays a major role in the control of cellular proliferation of many cell types. We studied the mitogenic effects of IGF-I, IGF-II, and epidermal growth factor (EGF) on growth-arrested HT-3 cells, a human cervical cancer cell line. All three growth factors promoted dose-dependent increases in cell proliferation. In untransformed cells, EGF usually requires stimulation by a "progression" factor such as IGF-I, IGF-II, or insulin (in supraphysiologic concentrations) in order to exert a mitogenic effect. Accordingly, we investigated whether an autocrine pathway involving IGF-I or IGF-II participated in the EGF-induced mitogenesis of HT-3 cells. With the RNase protection assay, IGF-I mRNA was not detected. However, IGF-II mRNA increased in a time-dependent manner following EGF stimulation. The EGF-induced mitogenesis was abrogated in a dose-dependent manner by IGF-binding protein 5 (IGFBP-5), which binds to IGF-II and neutralizes it. An antisense oligonucleotide to IGF-II also inhibited the proliferative response to EGF. In addition, prolonged, but not short-term, stimulation with EGF resulted in autophosphorylation of the IGF-I receptor, and coincubations with both EGF and IGFBP-5 attenuated this effect. These data demonstrate that autocrine secretion of IGF-II in HT-3 cervical cancer cells can participate in EGF-induced mitogenesis and suggest that autocrine signals involving the IGF-I receptor occur "downstream" of competence growth factor receptors such as the EGF receptor.