Da Jung

Vitamin C suppresses proliferation of the human melanoma cell SK-MEL-2 through the inhibition of cyclooxygenase-2 (COX-2) expression and the modulation of insulin-like growth factor II (IGF-II) production†

Vitamin C plays a crucial role in the suppression of proliferation of several types of cancer. Over‐expression of cyclooxygenase (COX)‐2 and type I insulin‐like growth factor (IGF) receptor are important for proliferation and protection from apoptosis in malignancies. However, its specific mechanisms, especially the interaction between COX‐2 expression and IGF‐I axis mediated by vitamin C, remain yet to be clarified. Therefore, we investigated the effects of vitamin C on the proliferation of melanoma cells via the modulation of COX‐2 expression and IGF‐I axis. As a result, we found that 1.0 mM vitamin C inhibits the proliferation of SK‐MEL‐2 without induction of apoptosis. At that moment, IGF‐II production was decreased, followed by the inhibition of COX‐2 activity. IGF‐IR expression was also down‐regulated by vitamin C treatment. It coincided with the result from the inhibition of COX‐2 by NS‐398 and COX‐2 siRNA. In addition, the decreased IGF‐IR expression by vitamin C was restored by the treatment of recombinant prostaglandin E2. Finally, we determined whether the signal pathway would be involved in vitamin C‐induced IGF‐II and IGF‐IR down‐regulation. When the cells were exposed to SB203580, a specific inhibitor of p38 MAPK, COX‐2 expression was dramatically recovered. In addition, phosphorylated p38 MAPK was increased after vitamin C treatment. Taken together, vitamin C suppresses proliferation of the human melanoma cell line SK‐MEL2 via the down‐regulation of IGF‐II production and IGF‐IR expression, which is followed by the activation of p38 MAPK and the inhibition of COX‐2 expression. J. Cell. Physiol. 216: 180–188, 2008.

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. J. Cell. Biochem. 102: 1002–1010, 2007.