Abstract
Gemcitabine (GEM) is currently used as a standard anticancer drug with the best evidence for pancreatic cancer. Recently we discovered that glycogen synthase kinase-3b (GSK-3b) promotes survival and proliferation of cancer cells and that combination of GEM and GSK-3b inhibitor (GSKI) is a putative therapeutic strategy for pancreatic cancer. In this study, we investigated the antitumor effect and molecular mechanisms of treatment by a GSKI combined with GEM. GEM (10-100 mg/L) and GSKI (AR-A014418; 5 mg/L, 16 µM) were added to the culture medium of the human pancreatic cancer cell line PANC-1 in vitro. Gene expression changes were analyzed with complementary DNA microarray and pathway analyses. Combination of GEM and GSKI synergistically suppressed the growth of PANC-1 cells dose-dependently in vitro. Complementary DNA microarray analysis demonstrated that expression of 372 genes was altered in GEM-treated PANC-1 cells. Ingenuity pathways analysis (IPA) revealed marked changes in the genes responsible for gene expression, cell death, DNA replication, and the cell cycle. In particular, IPA for GSKI-treated PANC-1 cells identified changes in expression of genes involved in both p53- and myc-related molecular networks. These data indicate that GSK-3b is a new therapeutic target in pancreatic cancer and that GSK-3b inhibition sensitizes pancreatic cancer cells to GEM by modulating p53 and myc pathways.
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Acknowledgements
We wish to thank Y. Ishigaki, K. Kawakami, T. Tanaka, and N. Tomosugi for their cooperation.
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© 2009 Springer-Verlag Berlin Heidelberg
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Motoo, Y., Shimasaki, T., Minamoto, T. (2009). Gemcitabine Changes the Gene Expression in Human Pancreatic Cancer Cells: Search for New Therapeutic Molecular Targets. In: Iovanna, J., Ismailov, U. (eds) Pancreatology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00152-9_4
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DOI: https://doi.org/10.1007/978-3-642-00152-9_4
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