Vitamin E inhibits cell proliferation and the activation of extracellular signal-regulated kinase during the promotion phase of lung tumorigenesis irrespective of antioxidative effect.
We have already reported that the activation of extracellular signal-regulated kinase (Erk) is critical in the stimulation of cell proliferation during the promotion stage of urethane-induced lung tumorigenesis in mice. Also, we have found that vitamin E suppresses lung tumorigenesis by inhibiting cell proliferation at the promotion stage. However, it is still unclear whether this inhibitory effect at the promotion stage is based on the antioxidative effect of vitamin E or not. In order to address this question, we examined the inhibitory effect of alpha-tocopheryloxybutyric acid (TSE), an ether derivative of vitamin E that cannot act as an antioxidant in vivo, on cell proliferation and the activation of Erk during promotion of lung tumorigenesis. On day 30 after urethane injection (750 mg/kg, i. p.) in A/J mice, TSE or vitamin E at 100 micromol/kg, p.o. was administered. Twenty-four hours after the final administration, the mice were killed to analyze cell proliferation and related parameters. The labeling index of proliferating cell nuclear antigen (a marker of cell proliferation) and ornithine decarboxylase activity (a marker of the promotion stage in lungs) were attenuated by treatment with TSE or vitamin E. TSE or vitamin E treatment also inhibited urethane-induced activation of Erk and suppressed the activation of other essential members of the Erk cascade (Ras, Raf and Mek). These results suggest that vitamin E inhibits cell proliferation and activation of the Erk cascade during promotion of urethane-induced lung tumorigenesis in mice, independent of its antioxidative effect.
Yano
T
T
Division of Applied Food Research, National Institute of Health and Nutrition, Tokyo, Japan.
Yajima
S
S
Hagiwara
K
K
Kumadaki
I
I
Yano
Y
Y
Otani
S
S
Uchida
M
M
Ichikawa
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D008805:Mice, Inbred A; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D014520:Urethane; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000975:Antioxidants; D002273:Carcinogens; D018809:Proliferating Cell Nuclear Antigen; C113106:tocopheryloxybutyric acid; D014810:Vitamin E; D014520:Urethane; D020928:Mitogen-Activated Protein Kinases; D009955:Ornithine Decarboxylase