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.
Krasil'nikov
M A
MA
Laboratory of Tumor Biochemistry, Institute of Carcinogenesis, Cancer Research Center, Kashirskoye shosse, 24, Moscow 115478, Russian Federation.
Shatskaya
V A
VA
Stavrovskaya
A A
AA
Erohina
M
M
Gershtein
E S
ES
Adler
V V
VV
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