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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.
J Pharmacol Exp Ther. 2009 Jun; 329(3):1063-70.JP

Abstract

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.

Authors+Show Affiliations

Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19258520

Citation

Yip-Schneider, Michele T., et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 329, no. 3, 2009, pp. 1063-70.
Yip-Schneider MT, Klein PJ, Wentz SC, et al. 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. J Pharmacol Exp Ther. 2009;329(3):1063-70.
Yip-Schneider, M. T., Klein, P. J., Wentz, S. C., Zeni, A., Menze, A., & Schmidt, C. M. (2009). 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. The Journal of Pharmacology and Experimental Therapeutics, 329(3), 1063-70. https://doi.org/10.1124/jpet.108.147306
Yip-Schneider MT, et al. 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. J Pharmacol Exp Ther. 2009;329(3):1063-70. PubMed PMID: 19258520.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Yip-Schneider,Michele T, AU - Klein,Patrick J, AU - Wentz,Sabrina C, AU - Zeni,Amer, AU - Menze,Alex, AU - Schmidt,C Max, Y1 - 2009/03/03/ PY - 2009/3/5/entrez PY - 2009/3/5/pubmed PY - 2009/6/24/medline SP - 1063 EP - 70 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 329 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/19258520/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_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=19258520 DB - PRIME DP - Unbound Medicine ER -