QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.147306v1 329/3/1063    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Yip-Schneider, M. T. Articles by Schmidt, C. M. PubMed PubMed Citation Articles by Yip-Schneider, M. T. Articles by Schmidt, C. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

CELLULAR AND MOLECULAR

Resistance to Mitogen-Activated Protein Kinase Kinase (MEK) Inhibitors Correlates with Up-Regulation of the MEK/Extracellular Signal-Regulated Kinase Pathway in Hepatocellular Carcinoma Cells

Departments of Surgery (M.T.Y.-S., P.J.K., S.C.W., A.Z., A.M., C.M.S.) and Biochemistry and Molecular Biology (C.M.S.), Indiana University Cancer Center (C.M.S.), Walther Oncology Center (C.M.S.), Indiana University School of Medicine, Indianapolis, Indiana; and Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana (C.M.S.)

The extracellular signal-regulated (ERK), mitogen-activated protein kinase (p42/p44 MAPK) pathway is up-regulated in hepatocellular carcinoma (HCC). Molecular targeting of this critical mitogenic pathway may have therapeutic potential for the treatment of HCC; however, chemoresistance to long-term therapy may develop. In the present study, we employed small-molecule MAPK kinase (MEK) inhibitors, including U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene] and PD184161 (Neoplasia 8:1–8, 2006), in HepG2 and Hep3B human HCC cell lines to identify potential mechanism(s) of resistance. U0126 dose-dependently suppressed ERK phosphorylation at both 1- and 24-h time points in HepG2 cells, previously shown to be sensitive to growth inhibition by U0126. In contrast, ERK phosphorylation was only decreased at the 1-h time point but not at 24 h in the more resistant Hep3B cells. It is interesting that the lack of prolonged phospho-ERK suppression was associated with MEK hyperphosphorylation in Hep3B cells. Several MEK/ERK pathway intermediates were up-regulated in Hep3B cells; furthermore, transfection of Raf-1 small interfering RNA to suppress MEK/ERK pathway activation sensitized Hep3B cells to U0126. MEK inhibitor resistance was independent of p53 or hepatitis Bx protein status. Finally, we showed that combining two chemically distinct MEK inhibitors enhanced growth inhibition and apoptosis compared with the single agents. Taken together, these results suggest that up-regulated expression or activity of the MEK/ERK pathway contributes to MEK inhibitor resistance in HCC cells. Our findings also provide preclinical evidence suggesting that the status of the MEK/ERK pathway in patients may predict response to MEK/ERK-targeted therapeutics.

Address correspondence to: C. Max Schmidt, Department of Surgery, Indiana University School of Medicine, 980 W. Walnut St., R4-C522, Indianapolis, IN 46202. E-mail: maxschmi{at}iupui.edu

This article has been cited by other articles:

				T. Miyake, N. S. Alli, A. Aziz, J. Knudson, P. Fernando, L. A. Megeney, and J. C. McDermott Cardiotrophin-1 Maintains the Undifferentiated State in Skeletal Myoblasts J. Biol. Chem., July 17, 2009; 284(29): 19679 - 19693. [Abstract] [Full Text] [PDF]