Role of GTP-binding proteins in reversing the antiproliferative effects of tocotrienols in preneoplastic mammary epithelial cells.
Tocotrienols are a subclass of vitamin E compounds that display potent anticancer activity. Determining the anticancer mechanism of action of tocotrienols will provide essential information necessary for understanding the potential health benefits of these compounds in reducing the risk of breast cancer in women. Epidermal growth factor (EGF) is a potent mitogen for normal and neoplastic mammary epithelial cells. Initial events in EGF-receptor (EGF-R) mitogenic-signalling are G-protein activation, stimulation of adenylyl cyclase and cyclic AMP (cAMP) production. Studies were conducted to determine if the antiproliferative effects of tocotrienols are associated with reduced EGF-induced G-protein and cAMP-dependent mitogenic signalling. Preneoplastic CL-S1 mouse mammary epithelial cells were grown in culture and maintained on serum-free media containing 0-25 micro mol/L tocotrienol-rich fraction of palm oil and/or different doses of pharmacological agents that alter intracellular cAMP levels. Tocotrienol-induced effects on EGF-receptor levels of tyrosine kinase activity, as well as EGF-dependent mitogen-activated pathway kinase (MAPK) and Akt activation, were determined by western blot analysis. Results demonstrate that the antiproliferative effects of tocotrienols in preneoplastic mammary epithelial cells do not reflect a reduction in EGF-receptor mitogenic responsiveness, but rather, result from an inhibition in early post-receptor events involved in cAMP production upstream from EGF-dependent MAPK and phosphoinositide 3-kinase/Akt mitogenic signalling. In summary, these data further characterise the mechanism of action of tocotrienols in suppressing preneoplastic mammary epithelial cell proliferation, and advance the current understanding of the potential health benefits of these compounds in reducing the risk of breast cancer in women.
Sylvester
Paul W
PW
College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0470, USA. pysylvester@ulm.edu
Nachnani
Anil
A
Shah
Sumit
S
Briski
Karen P
KP
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D024508:Tocotrienols / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D024508:Tocotrienols; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins