title: The molecular mechanisms of vitamin C on cell cycle regulation in B16F10 murine melanoma.
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.
authors: 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.
authors: Eunsil
authors: E
authors: Hahm
authors: Dong-Hoon
authors: DH
authors: Jin
authors: Jae Seung
authors: JS
authors: Kang
authors: Young-In
authors: YI
authors: Kim
authors: Seung-Woo
authors: SW
authors: Hong
authors: Seung Koo
authors: SK
authors: Lee
authors: Ha Na
authors: HN
authors: Kim
authors: Da Jung
authors: DJ
authors: Jung
authors: Jee Eun
authors: JE
authors: Kim
authors: Dong Hoon
authors: DH
authors: Shin
authors: Young Il
authors: YI
authors: Hwang
authors: Yeong Seok
authors: YS
authors: Kim
authors: Dae Young
authors: DY
authors: Hur
authors: Yoolhee
authors: Y
authors: Yang
authors: Daeho
authors: D
authors: Cho
authors: Myeong-Sok
authors: MS
authors: Lee
authors: Wang Jae
authors: WJ
authors: Lee
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D064447:Checkpoint Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D001205:Ascorbic Acid