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

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

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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-KB, 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.

Original languageEnglish (US)
Pages (from-to)455-465
Number of pages11
JournalCancer Prevention Research
Volume6
Issue number5
DOIs
StatePublished - May 2013

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