title: 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.
abstract: 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.
authors.affiliation: Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Seung Koo
authors.initials: SK
authors.lastname: Lee
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Kang
authors.forename: Da Jung
authors.initials: DJ
authors.lastname: Jung
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hur
authors.forename: Jee Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Eunsil
authors.initials: E
authors.lastname: Hahm
authors.forename: Seyeon
authors.initials: S
authors.lastname: Bae
authors.forename: Hyung Woo
authors.initials: HW
authors.lastname: Kim
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
authors.forename: Byung Joo
authors.initials: BJ
authors.lastname: Cho
authors.forename: Daeho
authors.initials: D
authors.lastname: Cho
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Shin
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Hwang
authors.forename: Wang Jae
authors.initials: WJ
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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