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Direct targeting of MEK1/2 and RSK2 by silybin induces cell-cycle arrest and inhibits melanoma cell growth.
Cancer Prev Res (Phila) 2013; 6(5):455-65CP

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+Show Affiliations

Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23447564

Citation

Lee, Mee-Hyun, et al. "Direct Targeting of MEK1/2 and RSK2 By Silybin Induces Cell-cycle Arrest and Inhibits Melanoma Cell Growth." Cancer Prevention Research (Philadelphia, Pa.), vol. 6, no. 5, 2013, pp. 455-65.
Lee MH, Huang Z, Kim DJ, et al. Direct targeting of MEK1/2 and RSK2 by silybin induces cell-cycle arrest and inhibits melanoma cell growth. Cancer Prev Res (Phila). 2013;6(5):455-65.
Lee, M. H., Huang, Z., Kim, D. J., Kim, S. H., Kim, M. O., Lee, S. Y., ... Dong, Z. (2013). Direct targeting of MEK1/2 and RSK2 by silybin induces cell-cycle arrest and inhibits melanoma cell growth. Cancer Prevention Research (Philadelphia, Pa.), 6(5), pp. 455-65. doi:10.1158/1940-6207.CAPR-12-0425.
Lee MH, et al. Direct Targeting of MEK1/2 and RSK2 By Silybin Induces Cell-cycle Arrest and Inhibits Melanoma Cell Growth. Cancer Prev Res (Phila). 2013;6(5):455-65. PubMed PMID: 23447564.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Direct targeting of MEK1/2 and RSK2 by silybin induces cell-cycle arrest and inhibits melanoma cell growth. AU - Lee,Mee-Hyun, AU - Huang,Zunnan, AU - Kim,Dong Joon, AU - Kim,Sung-Hyun, AU - Kim,Myoung Ok, AU - Lee,Sung-Young, AU - Xie,Hua, AU - Park,Si Jun, AU - Kim,Jae Young, AU - Kundu,Joydeb Kumar, AU - Bode,Ann M, AU - Surh,Young-Joon, AU - Dong,Zigang, Y1 - 2013/02/27/ PY - 2013/3/1/entrez PY - 2013/3/1/pubmed PY - 2013/12/20/medline SP - 455 EP - 65 JF - Cancer prevention research (Philadelphia, Pa.) JO - Cancer Prev Res (Phila) VL - 6 IS - 5 N2 - 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. SN - 1940-6215 UR - https://www.unboundmedicine.com/medline/citation/23447564/Direct_targeting_of_MEK1/2_and_RSK2_by_silybin_induces_cell_cycle_arrest_and_inhibits_melanoma_cell_growth_ L2 - http://cancerpreventionresearch.aacrjournals.org/cgi/pmidlookup?view=long&pmid=23447564 DB - PRIME DP - Unbound Medicine ER -