Role of phosphatidylinositol signaling pathway in the development of cross-resistance of tumor cells to hormonal cytostatics and hypoxia

Long-term in vitro culturing of CaOv ovarian adenocarcinoma cells in the presence of a synthetic analogue of glucocorticoid hormone dexamethasone allowed us to obtain a subline of CaOv/D cells resistant to the antiproliferative effect of dexamethasone and characterized by high resistance to hypoxia. It was found that CaOv/D cells are characterized by constitutive increase in phosphatidylinositol 3-kinase expression and hypersecretion of vascular endothelial growth factor VEGF-A. Culturing of cells under hypoxic conditions was accompanied by a significant increase in phosphatidylinositol 3-kinase expression and VEGF-A synthesis. Experiments with cell transfection with phosphatidylinositol 3-kinase catalytic subunit proved its participation in the regulation of VEGF-A synthesis and maintenance of cell growth under condition of hypoxia. Our results indicate that coordinated activation of phosphatidylinositol 3-kinase and VEGF-A can be a factor determining the development of cross-resistance of tumor cells to hormonal cytostatics and hypoxia.