Abstract
Although gemcitabine is the most commonly used drug for treating pancreatic cancers, acquired gemcitabine resistance in a substantial number of patients appears to hinder its effectiveness in successful treatment of this dreadful disease. To understand acquired gemcitabine resistance, we generated a gemcitabine-resistant pancreatic cancer cell line using stepwise selection and found that, in addition to the known mechanisms of up-regulated expression of ribonucleotide reductase, 14-3-3σ expression is dramatically up-regulated and that 14-3-3σ over-expression contributes to the acquired resistance to gemcitabine and cross resistance to Ara-C. We also found that the increased 14-3-3σ expression in the gemcitabine-resistant cells is due to demethylation of the 14-3-3σ gene during gemcitabine selection, which could be partially reversed with removal of the gemcitabine selection pressure. Most importantly, the reversible methylation/demethylation of the 14-3-3σ gene appears to be carried out by DNMT1 under the regulation by Uhrf1. These findings suggest that the epigenetic regulation of gene expression may play an important role in gemcitabine resistance and that epigenetic modification is reversible in response to gemcitabine treatment.
- The American Society for Pharmacology and Experimental Therapeutics