The molecular mechanisms of vitamin C on cell cycle regulation in B16F10 murine melanoma.
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.
Hahm
Eunsil
E
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.
Jin
Dong-Hoon
DH
Kang
Jae Seung
JS
Kim
Young-In
YI
Hong
Seung-Woo
SW
Lee
Seung Koo
SK
Kim
Ha Na
HN
Jung
Da Jung
DJ
Kim
Jee Eun
JE
Shin
Dong Hoon
DH
Hwang
Young Il
YI
Kim
Yeong Seok
YS
Hur
Dae Young
DY
Yang
Yoolhee
Y
Cho
Daeho
D
Lee
Myeong-Sok
MS
Lee
Wang Jae
WJ
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
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