Vitamin E inhibition of normal mammary epithelial cell growth is associated with a reduction in protein kinase C(alpha) activation.
Tocopherols and tocotrienols represent the two subclasses within the vitamin E family of compounds. However, tocotrienols are significantly more potent than tocopherols in suppressing epidermal growth factor (EGF)-dependent normal mammary epithelial cell growth. EGF is a potent mitogen for normal mammary epithelial cells and an initial event in EGF-receptor mitogenic-signalling is protein kinase C (PKC) activation. Studies were conducted to determine if the antiproliferative effects of specific tocopherol and tocotrienol isoforms are associated with a reduction in EGF-receptor mitogenic signalling and/or PKC activation. Normal mammary epithelial cells isolated from midpregnant BALB/c mice were grown in primary culture, and maintained on serum-free media containing 10 ng/mL EGF as a mitogen, and treated with various doses (0-250 microm) of alpha-, gamma-, or delta-tocopherol or alpha-, gamma-, or delta-tocotrienol. Treatment with growth inhibitory doses of delta-tocopherol (100 microm), alpha-tocotrienol (50 microm), or gamma- or delta-tocotrienol (10 microm) did not affect EGF-receptor levels, EGF-induced EGF-receptor tyrosine kinase activity, or total intracellular levels of PKC(alpha). However, these treatments were found to inhibit EGF-induced PKC(alpha) activation as determined by its translocation from the cytosolic to membrane fraction. Treatment with 250 microm alpha- or gamma-tocopherol had no affect on EGF-receptor mitogenic signalling or cell growth. These findings demonstrate that the inhibitory effects of specific tocopherol and tocotrienol isoforms on EGF-dependent normal mammary epithelial cell mitogenesis occurs downstream from the EGF-receptor and appears to be mediated, at least in part, by a reduction in PKC(alpha) activation.
Sylvester
P W
PW
College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0470, USA. pysylvester@ulm.edu
McIntyre
B S
BS
Gapor
A
A
Briski
K P
KP
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism*; D013997:Time Factors; D024508:Tocotrienols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000494:pharmacology; D024504:gamma-Tocopherol / Q000494:pharmacology
D002839:Chromans; D024508:Tocotrienols; D014810:Vitamin E; C082097:tocotrienol, delta; C013649:plastochromanol 8; D004815:Epidermal Growth Factor; D024504:gamma-Tocopherol; C082032:tocotrienol, alpha; D011493:Protein Kinase C; D024502:alpha-Tocopherol