The molecular mechanisms of vitamin C on cell cycle regulation in B16F10 murine melanoma |
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Authors: | Hahm Eunsil Jin Dong-Hoon Kang Jae Seung Kim Young-In Hong Seung-Woo Lee Seung Koo Kim Ha Na Jung Da Jung Kim Jee Eun Shin Dong Hoon Hwang Young Il Kim Yeong Seok Hur Dae Young Yang Yoolhee Cho Daeho Lee Myeong-Sok Lee Wang Jae |
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Affiliation: | Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-799, South Korea. |
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Abstract: | Vitamin C has inconsistent effects on malignant tumor cells, which vary from growth stimulation to apoptosis induction. It is well known that melanoma cells are more susceptible to vitamin C than any other tumor cells, but the precise mechanism remains to be elucidated. In the present study, the proliferation of B16F10 melanoma cells was suppressed by vitamin C, which induced growth arrest in a dose-dependent manner without cytotoxic effects. Therefore, we investigated the changes in cell cycle distribution of B16F10 melanoma cells by staining DNAs with propidium iodide (PI). The growth inhibition of B16F10 melanoma by vitamin C was associated with an arrest of cell cycle distribution at G1 stage. In addition, the levels of p53-p21Waf1/Cip1 increased during G1 arrest, which were essential for vitamin C-induced cell cycle arrest. The increased p21Waf1/Cip1 inhibited CDK2. Moreover, the activity of p53-p21Waf1/Cip1 pathway was closely related with the activation of checkpoint kinase 2 (Chk2). Inhibitor of the PI3K-family, LY294002 and the ATM/ATR inhibitor, caffeine, blocked vitamin C-induced growth arrest in B16F10 melanoma cells. These results suggest that vitamin C might be a potent agent to inhibit proliferative activity of melanoma cells via the regulation of Chk2-p53-p21Waf1/Cip1 pathway. |
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Keywords: | G1 arrest vitamin C melanoma p53 p21Waf1/Cip1 Chk2 CDK2 |
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