Inhibition of granulosa cell differentiation by dioctanoylglycerol--a novel activator of protein kinase C.
The actions of dioctanoylglycerol, a novel and specific activator of protein kinase C, on granulosa cell steroidogenesis and LH/hCG receptor induction were examined in vitro. Granulosa cells were cultured for 2 days in media containing 100 nM androstenedione. FSH treatment stimulated progesterone, 20 alpha-hydroxy-pregn-4-en-3-one (20 alpha-OH-P) and estrogen production by 60- to 80-fold over basal levels. Treatment with dioctanoylglycerol increased progesterone production 3-fold over basal levels but failed to affect 20 alpha-OH-P or estrogen production. Concomitant treatment of cells with FSH and increasing amounts of dioctanoylglycerol produced dose-dependent inhibition of FSH-stimulated progesterone, 20 alpha-OH-P and estrogen production with IC50 values of 75, 40 and 50 microM, respectively. Dioctanoylglycerol also inhibited production of all three steroids induced by forskolin, an activator of adenylate cyclase, and dibutyryl cAMP. The effects of dioctanoylglycerol on cAMP responses to FSH were also examined. The increase in both intracellular and extracellular cAMP at 1 h following treatment with FSH was suppressed in the presence of dioctanoylglycerol as was the extracellular accumulation of cAMP at 48 h of culture. FSH induction of LH/hCG receptors, known to be a cAMP-mediated event, was also inhibited in the presence of dioctanoylglycerol. In contrast, a thio-derivative of dioctanoylglycerol (3-thio-1,2-dioctanoylglycerol), which does not activate protein kinase C, failed to inhibit both steroidogenesis and LH/hCG receptor induction in response to FSH.(ABSTRACT TRUNCATED AT 250 WORDS)
Kasson
B G
BG
Conn
P M
PM
Hsueh
A J
AJ
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D005576:Colforsin; D000242:Cyclic AMP / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004967:Estrogens / Q000096:biosynthesis; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology*; D006107:Granulosa Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D006908:Hydroxyprogesterones / Q000096:biosynthesis; D011374:Progesterone / Q000096:biosynthesis; D011493:Protein Kinase C; D011494:Protein Kinases / Q000502:physiology*; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D011974:Receptors, LH
D004075:Diglycerides; D004224:Diterpenes; D004967:Estrogens; D005989:Glycerides; D006908:Hydroxyprogesterones; D011956:Receptors, Cell Surface; D011974:Receptors, LH; C044295:1,2-dioctanoylglycerol; D005576:Colforsin; D011374:Progesterone; D003994:Bucladesine; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D011494:Protein Kinases; D011493:Protein Kinase C