Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction in IGF binding proteins
| Autor: | Michael Danilenko, D LeRoith, Yoav Sharoni, Dita Kleinman, Michael Karas, A Arbell, C T Roberts, Joseph Levy |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
medicine.medical_specialty
Antineoplastic Agents Hormonal medicine.drug_class medicine.medical_treatment Receptor IGF Type 1 chemistry.chemical_compound Insulin-like growth factor Endocrinology Piperidines Internal medicine Tumor Cells Cultured medicine Humans Growth factor receptor inhibitor Insulin-Like Growth Factor I Phosphorylation skin and connective tissue diseases Autocrine signalling biology Chemistry Estrogen Antagonists Tyrosine phosphorylation Antiestrogen Endometrial Neoplasms Insulin-Like Growth Factor Binding Proteins Tamoxifen Estrogen Raloxifene Hydrochloride biology.protein Cancer research Tyrosine Female Cell Division hormones hormone substitutes and hormone antagonists Platelet-derived growth factor receptor medicine.drug |
| Zdroj: | Endocrinology. 137:1089-1095 |
| ISSN: | 1945-7170 0013-7227 |
| Popis: | A significant increase in endometrial cancer incidence in tamoxifen-treated breast cancer patients has been reported in many recent studies. The major growth stimulators of endometrial tumors are estrogens, but paradoxically, tamoxifen, a known antiestrogen, also stimulates their growth. The mode of action of estrogen can be partially explained by the modulation of insulin-like growth factor (IGF) autocrine or paracrine action. The purpose of the present study was to examine the involvement of the IGF system in the tamoxifen-stimulated growth of Ishikawa endometrial cancer cells by quantitating the IGF-I receptors and their phosphorylation, as well as membrane associated and secreted IGF-binding proteins (IGFBPs). Tamoxifen did not affect the number or affinity of IGF-I receptors. On the other hand, tamoxifen, similar to estradiol, increased IGF-I-stimulated tyrosine phosphorylation of cellular substrates. In contrast, in MCF-7 mammary cancer cells, tamoxifen reduced IGF-induced tyrosine phosphorylation in the presence of estradiol. The pure antiestrogen LY156758 did not affect Ishikawa basal cell growth but inhibited estradiol- and tamoxifen-induced growth. Growth inhibition by LY156758 of tamoxifen and estradiol-stimulated cells was accompanied by a corresponding inhibition of IGF-stimulated tyrosine phosphorylation. Tamoxifen caused a 3-fold decrease in membrane-associated IGFBPs. Moreover, a reduction in soluble IGFBPs was also observed, making the IGF peptides more available to the receptors. A parallel decrease in IGFBP-3 mRNA was also detected. These experiments suggest that tamoxifen, like estradiol, directly sensitizes endometrial cancer cells to the effects of IGFs that act through the type I receptor. Furthermore, the decrease in IGFBPs and the increase in tyrosine phosphorylation in the presence of tamoxifen provides a molecular mechanism that accounts for the uterotropic effects that are seen with tamoxifen therapy. |
| Databáze: | OpenAIRE |
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