Selenium Inhibits Metastasis of Murine Melanoma Cells through the Induction of Cell Cycle Arrest and Cell Death

Background Melanoma is the most fatal form of skin cancer due to its rapid metastasis. Recently, several studies reported that selenium can induce apoptosis in melanoma cells. However, the precise mechanism remains to be elucidated. In this study, we investigated the effect of selenium on cell proliferation in murine melanoma and on tumor growth and metastasis in C57BL/6 mice. Methods Cell proliferation was measured by MTT assay in selenium-treated melanoma cells. Cell cycle distribution was analysized by staining DNA with propidum iodide (PI). mRNA and protein expression related to cell cycle arrest was measured by reverse transcription PCR and western blot. Tumor growth and metastasis was measured by in vivo model. Results Selenium was suppressed the proliferation of melanoma cells in a dose dependent manner. The growth inhibition of melanoma by selenium was associated with an arrest of cell cycle distribution at G0/G1 stage. The mRNA and protein level of CDK2/CDK4 was suppressed by treatment with selenium in a time-dependent manner. In vivo, tumor growth was not suppressed by selenium; however tumor metastasis was suppressed by selenium in mouse model. Conclusion These results suggest that selenium might be a potent agent to inhibit proliferative activity of melanoma cells.

[1]  M. Červinka,et al.  Selenium activates p53 and p38 pathways and induces caspase-independent cell death in cervical cancer cells , 2008, Cell Biology and Toxicology.

[2]  Kam Y. J. Zhang,et al.  Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity , 2008, Proceedings of the National Academy of Sciences.

[3]  P. Kuo,et al.  Plumbagin induces cell cycle arrest and apoptosis through reactive oxygen species/c-Jun N-terminal kinase pathways in human melanoma A375.S2 cells. , 2008, Cancer letters.

[4]  Seung-Woo Hong,et al.  The molecular mechanisms of vitamin C on cell cycle regulation in B16F10 murine melanoma , 2007, Journal of cellular biochemistry.

[5]  Nizar M. Mhaidat,et al.  Temozolomide induces senescence but not apoptosis in human melanoma cells , 2007, British Journal of Cancer.

[6]  A. Ingle,et al.  Suramin augments the antitumor and antimetastatic activity of pentoxifylline in B16F10 melanoma , 2007, International journal of cancer.

[7]  Eun Hee Kim,et al.  Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. , 2007, Cancer research.

[8]  Yang Yang,et al.  Requirement for ERK activity in sodium selenite-induced apoptosis of acute promyelocytic leukemia-derived NB4 cells. , 2007, Journal of biochemistry and molecular biology.

[9]  N. Traynor,et al.  Selenomethionine inhibits ultraviolet radiation‐induced p53 transactivation , 2006, Photodermatology, photoimmunology & photomedicine.

[10]  M. Rath,et al.  INHIBITION OF PULMONARY METASTASIS OF MELANOMA B16FO CELLS IN C57BL/6 MICE BY A NUTRIENT MIXTURE CONSISTING OF ASCORBIC ACID, LYSINE, PROLINE, ARGININE, AND GREEN TEA EXTRACT , 2006, Experimental lung research.

[11]  T. Ikejima,et al.  Mitogen-activated protein kinase-dependent apoptosis in norcan-tharidin-treated A375-S2 cells is proceeded by the activation of protein kinase C. , 2005, Chinese medical journal.

[12]  Lyn Patrick,et al.  Selenium biochemistry and cancer: a review of the literature. , 2004, Alternative medicine review : a journal of clinical therapeutic.

[13]  Cheng Jiang,et al.  Selenite-induced p53 Ser-15 phosphorylation and caspase-mediated apoptosis in LNCaP human prostate cancer cells. , 2004, Molecular cancer therapeutics.

[14]  Huibi Xu,et al.  Both calcium and ROS as common signals mediate Na(2)SeO(3)-induced apoptosis in SW480 human colonic carcinoma cells. , 2003, Journal of inorganic biochemistry.

[15]  Qiang Yu,et al.  A p53-independent G1 Cell Cycle Checkpoint Induced by the Suppression of Protein Kinase C α and θ Isoforms* , 2003, Journal of Biological Chemistry.

[16]  K. Vermeulen,et al.  The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer , 2003, Cell proliferation.

[17]  A. Chung,et al.  Se-methylselenocysteine induces apoptosis mediated by reactive oxygen species in HL-60 cells. , 2001, Free radical biology & medicine.

[18]  Tae‐Ho Kim,et al.  Se-methylselenocysteine induces apoptosis through caspase activation in HL-60 cells. , 2001, Carcinogenesis.

[19]  I. Saiki,et al.  Tumor invasion is inhibited by phosphorylated ascorbate via enrichment of intracellular vitamin C and decreasing of oxidative stress , 2000, Journal of Cancer Research and Clinical Oncology.

[20]  F. Traganos,et al.  Cell cycle arrest and apoptosis of melanoma cells by docosahexaenoic acid: association with decreased pRb phosphorylation. , 2000, Cancer research.

[21]  C. Sherr The Pezcoller lecture: cancer cell cycles revisited. , 2000, Cancer research.

[22]  G. Combs,et al.  Chemopreventive agents: selenium. , 1998, Pharmacology & therapeutics.

[23]  J. Roth,et al.  p53 expression overcomes p21WAF1/CIP1-mediated G1 arrest and induces apoptosis in human cancer cells , 1997, Oncogene.

[24]  R. Strange,et al.  Differential induction of growth arrest inducible genes by selenium compounds. , 1997, Biochemical pharmacology.

[25]  I. Herskowitz,et al.  Joining the complex: Cyclin-dependent kinase inhibitory proteins and the cell cycle , 1994, Cell.

[26]  G. F. Kramer,et al.  Mechanisms of mutagenicity and toxicity of sodium selenite (Na2SeO3) in Salmonella typhimurium. , 1988, Mutation research.

[27]  Qiang Yu,et al.  A p53-independent G1 cell cycle checkpoint induced by the suppression of protein kinase C alpha and theta isoforms. , 2003, The Journal of biological chemistry.

[28]  M. Herlyn,et al.  Tumor progression in melanoma: the biology of epidermal melanocytes in vitro. , 1989, Carcinogenesis; a comprehensive survey.