The role of phosphatidylinositol 3-kinase in the regulation of cell response to steroid hormones.
Phosphatidylinositol 3-kinase (PI-3 kinase) has been implicated in the regulation of many cellular processes, including growth and transformation. We describe the effect of glucocorticoids on cell growth, phosphoinositide formation and PI-3 kinase activity in Rous sarcoma virus-transformed hamster fibroblasts (HET-SR). Using a prolonged dexamethasone treatment of HET-SR cells we have selected a new glucocorticoid receptor-positive cell subline, HET-SR(h), that was resistant to growth inhibitory action of dexamethasone and/or non-hormonal drugs (vinblastine, adriamycin) and was characterized by higher levels of phosphoinositide formation and increased PI-3 kinase activity. Study of the short-term hormone action has shown that both dexamethasone-sensitive and -resistant sublines responded to hormone by a decrease in phospholipid turnover rate. At the same time, in both cell lines activation of PI-3 kinase after dexamethasone addition was revealed. Dexamethasone-dependent activation of PI-3 kinase was more significant and maintained for a longer period in HET-SR(h) cells than in parent HET-SR cells. Finally, by transfecting p110*, a constitutively active catalytic subunit of PI-3 kinase, into hormone-sensitive HET-SR cells, we have found a marked increase in cell resistance to growth inhibitory dexamethasone action. These results suggest that PI-3 kinase may serve as one of the factors providing cell resistance to cytostatic drugs.
Laboratory of Tumor Biochemistry, Institute of Carcinogenesis, Cancer Research Center, Kashirskoye shosse, 24, Moscow 115478, Russian Federation.
M A
MA
Krasil'nikov
V A
VA
Shatskaya
A A
AA
Stavrovskaya
M
M
Erohina
E S
ES
Gershtein
V V
VV
Adler
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival; D006224:Cricetinae; D003907:Dexamethasone / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000032:analysis; D013997:Time Factors; D014162:Transfection; D014747:Vinblastine / Q000494:pharmacology
D005938:Glucocorticoids; D010716:Phosphatidylinositols; D011965:Receptors, Glucocorticoid; D014747:Vinblastine; D003907:Dexamethasone; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases