INSULIN-LIKE-GROWTH-FACTOR-II MEDIATES EPIDERMAL GROWTH FACTOR-INDUCED MITOGENESIS IN CERVICAL-CANCER CELLS

There is increasing evidence that activation of the insulin-like growt h factor I (IGF-I) receptor plays a major role in the control of cellu lar proliferation of many cell types. We studied the mitogenic effects of IGF-I, IGF-II, and epidermal growth factor (EGF) on growth-arreste d HT-3 cells, a human cervical cancer cell line. All three growth fact ors promoted dose-dependent increases in cell proliferation. In untran sformed cells, EGF usually requires stimulation by a ''progression'' f actor such as IGF-I, IGF-II, or insulin (in supraphysiologic concentra tions) in order to exert a mitogenic effect. Accordingly, we investiga ted whether an autocrine pathway involving IGF-I or IGF-II participate d in the EGF-induced mitogenesis of HT-3 cells. With the RNase protect ion 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 p rotein 5 (IGFBP-5), which binds to IGF-II and neutralizes it. An antis ense oligonucleotide to IGF-II also inhibited the proliferative respon se to EGF. In addition, prolonged, but not short-term, stimulation wit h EGF resulted in autophosphorylation of the IGF-I receptor, and coinc ubations 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 aut ocrine signals involving the IGF-I receptor occur ''downstream'' of co mpetence growth factor receptors such as the EGF receptor.