Open AccessERK1/2 activity contributes to gemcitabine resistance in pancreatic cancer cells
Author(s) -
ChaoHui Zheng,
Xuelong Jiao,
Yunpeng Jiang,
Song Sun
Publication year - 2013
Publication title -
journal of international medical research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.421
H-Index - 57
eISSN - 1473-2300
pISSN - 0300-0605
DOI - 10.1177/0300060512474128
Subject(s) - gemcitabine , pancreatic cancer , apoptosis , mapk/erk pathway , cancer research , medicine , kinase , cell culture , cell growth , chemotherapy , cancer , biology , microbiology and biotechnology , biochemistry , genetics
Objective To test the hypothesis that chemoresistance in pancreatic cancer is mediated via extracellular signal-regulated protein kinase (ERK) 1/2 overactivity.Methods The human pancreatic cancer cell lines BxPC3, PANC-1 and a stably gemcitabine-resistant subline, PANC1 GemRes , were treated with combinations of gemcitabine and the ERK1/2 inhibitor, U0126. Phosphorylated (p)ERK1/2 was examined by Western blotting; cell proliferation and apoptosis were quantified. A nude mouse xenograft model was established with each cell line, and the therapeutic efficacy of gemcitabine and U0126 alone or in combination was examined.Results Gemcitabine treatment visibly increased pERK1/2 levels in BxPC-3 and PANC-1 cells. PANC-1 GemRes constitutively produced high levels of pERK1/2. U0126 treatment reversed the gemcitabine-associated increase in cell proliferation and reduction in apoptosis, in all three cell lines. Combination treatment with U0126 and gemcitabine inhibited tumour growth and promoted apoptosis in xenograft tumours derived from all three cell lines.Conclusions ERK1/2 activity may protect pancreatic cancer cells from chemotherapy-induced apoptosis. The combined use of an ERK1/2 inhibitor (such as U0126) together with gemcitabine may result in synergistic therapeutic effects at tolerable gemcitabine doses.