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.
Lee
Seung Koo
SK
Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.
Kang
Jae Seung
JS
Jung
Da Jung
DJ
Hur
Dae Young
DY
Kim
Jee Eun
JE
Hahm
Eunsil
E
Bae
Seyeon
S
Kim
Hyung Woo
HW
Kim
Daejin
D
Cho
Byung Joo
BJ
Cho
Daeho
D
Shin
Dong Hoon
DH
Hwang
Young-Il
YI
Lee
Wang Jae
WJ
D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D014815:Vitamins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D014815:Vitamins; D007335:Insulin-Like Growth Factor II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017526:Receptor, IGF Type 1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D001205:Ascorbic Acid