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: Eunsil Hahm, Dong-Hoon Jin, Jae Seung Kang, Young-In Kim, Seung-Woo Hong, Seung Koo Lee, Ha Na Kim, Da Jung Jung, Jee Eun Kim, Dong Hoon Shin, Young Il Hwang, Yeong Seok Kim, Dae Young Hur, Yoolhee Yang, Daeho Cho, Myeong-Sok Lee, Wang Jae Lee
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 102 Issue 4 Pg. 1002-10 (Nov 01 2007) ISSN: 0730-2312 [Print] United States
• PMID: 17455238 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2007 Wiley-Liss, Inc.

Chemical References

• Cdkn1a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p21
• Tumor Suppressor Protein p53
• Checkpoint Kinase 2
• Chek2 protein, mouse
• Protein Serine-Threonine Kinases
• Ascorbic Acid

Topics

• Animals
• Ascorbic Acid (pharmacology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Checkpoint Kinase 2
• Cyclin-Dependent Kinase Inhibitor p21
• Dose-Response Relationship, Drug
• G1 Phase (drug effects)
• Melanoma, Experimental (drug therapy, pathology)
• Mice
• Protein Serine-Threonine Kinases
• Signal Transduction
• Tumor Suppressor Protein p53