Vitamin E inhibits cell proliferation and the activation of extracellular signal-regulated kinase during the promotion phase of lung tumorigenesis irrespective of antioxidative effect

• Published in: Carcinogenesis (New York) 2000-11, Vol.21 (11), p.2129-2133
• Main Authors: Yano, Tomohiro, Yajima, Shoko, Hagiwara, Kiyokazu, Kumadaki, Itsumaro, Yano, Yoshihisa, Otani, Shuzo, Uchida, Mikako, Ichikawa, Tomio
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antioxidants - pharmacology; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens; Cell Division - drug effects; Chemical agents; EGFR; Enzyme Activation - drug effects; epidermal growth factor receptor; Erk; Erk kinase; extracellular signal-regulated kinase; Female; labeling index; Lung Neoplasms - chemically induced; Lung Neoplasms - enzymology; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Medical sciences; Mice; Mice, Inbred A; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; ODC; ornithine decarboxylase; Ornithine Decarboxylase - metabolism; PCNA; proliferating cell nuclear antigen; Proliferating Cell Nuclear Antigen - metabolism; TSE; Tumors; Urethane; Vitamin E - analogs & derivatives; Vitamin E - pharmacology; α-tocopheryloxybutyric acid
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/21.11.2129

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 α-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 μmol/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.