Pancreatic
adenocarcinoma is one of the
malignancies that is highly resistant to
therapy and among the leading causes of
cancer-related death. Several factors may influence
pancreatic cancer resistance, and expression of
ATP-binding cassette
transport proteins is one of the major mechanisms of drug resistance. Members of this family's C-branch, also referred to as
multidrug resistance-associated proteins (MRPs), might be of particular interest because they are able to efflux
nucleoside analogs used in the treatment of
pancreatic cancer. Expression of
MRP1, MRP3, MRP4, and MRP5 in human pancreas and
pancreatic carcinoma has been reported. However, contributions of MRPs to chemoresistance of
pancreatic cancer are not fully understood. MRP5
mRNA expression in pancreatic
adenocarcinoma cell lines correlated significantly with cellular sensitivity to
5-fluorouracil (5-FU) (r = 0.738, p < 0.05). Long-term treatment with
5-FU increased expression of MRP5 by 2.4-fold and was associated with significant drug resistance [IC(50) values for control and
5-fluorouracil (5-FU)-resistant Patu-T cell lines were 11.3 ± 5.3 and 33.2 ± 6.9 μM, respectively (p < 0.05)]. Consequently, overexpression of MRP5 in Colo-357 cells resulted in significantly reduced accumulation of
5-FU related radioactivity and
5-FU cytotoxicity. Knockdown of MRP5 significantly increased cellular cytotoxicity of
5-FU to Patu-02 cells and enhanced accumulation of radioactivity related to
5-FU and its metabolites. Our results suggest that MRP5 is expressed and functionally active and contributes to variable sensitivities of pancreatic
adenocarcinoma cell lines to
5-FU. Further investigations using models that resemble human pancreas
tumors are necessary to prove a causative relation between expression and activity of MRP5 and
tumor resistance to
5-FU.