Direct targeting of MEK1/2 and RSK2 by silybin induces cell-cycle arrest and inhibits melanoma cell growth.

Abstract

Abnormal functioning of multiple gene products underlies the neoplastic transformation of cells. Thus, chemopreventive and/or chemotherapeutic agents with multigene targets hold promise in the development of effective anticancer drugs. Silybin, a component of milk thistle, is a natural anticancer agent. In the present study, we investigated the effect of silybin on melanoma cell growth and elucidated its molecular targets. Our study revealed that silybin attenuated the growth of melanoma xenograft tumors in nude mice. Silybin inhibited the kinase activity of mitogen-activated protein kinase (MEK)-1/2 and ribosomal S6 kinase (RSK)-2 in melanoma cells. The direct binding of silybin with MEK1/2 and RSK2 was explored using a computational docking model. Treatment of melanoma cells with silybin attenuated the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and RSK2, which are regulated by the upstream kinases MEK1/2. The blockade of MEK1/2-ERK1/2-RSK2 signaling by silybin resulted in a reduced activation of NF-κB, activator protein-1, and STAT3, which are transcriptional regulators of a variety of proliferative genes in melanomas. Silybin, by blocking the activation of these transcription factors, induced cell-cycle arrest at the G1 phase and inhibited melanoma cell growth in vitro and in vivo. Taken together, silybin suppresses melanoma growth by directly targeting MEK- and RSK-mediated signaling pathways.

• Authors: Mee-Hyun Lee, Zunnan Huang, Dong Joon Kim, Sung-Hyun Kim, Myoung Ok Kim, Sung-Young Lee, Hua Xie, Si Jun Park, Jae Young Kim, Joydeb Kumar Kundu, Ann M Bode, Young-Joon Surh, Zigang Dong
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 6 Issue 5 Pg. 455-65 (May 2013) ISSN: 1940-6215 [Electronic] United States
• PMID: 23447564 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Enzyme Inhibitors
• Silymarin
• Silybin
• Ribosomal Protein S6 Kinases, 90-kDa
• ribosomal protein S6 kinase, 90kDa, polypeptide 3
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• Map2k1 protein, mouse
• Map2k2 protein, mouse

Topics

• Animals
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Computer Simulation
• Enzyme Inhibitors (pharmacology)
• Female
• G1 Phase (drug effects)
• Heterografts
• Humans
• Immunoenzyme Techniques
• MAP Kinase Kinase 1 (chemistry, metabolism)
• MAP Kinase Kinase 2 (chemistry, metabolism)
• Melanoma, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Protein Conformation
• Ribosomal Protein S6 Kinases, 90-kDa (chemistry, metabolism)
• Silybin
• Silymarin (pharmacology)
• Tumor Cells, Cultured