The Ras/Raf/
MEK/ERK signaling has been implicated in uncontrolled cell proliferation and
tumor progression in
pancreatic cancer. The purpose of this study is to evaluate the antitumor activity of
MEK inhibitor
U0126 in combination with Hsp90 inhibitor
17-allylamino-17-demethoxygeldanamycin (17-AAG) in
pancreatic cancer cells. Western blotting showed that
17-AAG caused a 2- to 3-fold transient activation of
MEK/ERK signaling in
pancreatic cancer cells. The activation sustained for 6 h before phospho-ERK (p-ERK) destabilization. The selective
MEK inhibitor
U0126 completely abolished
17-AAG induced ERK1/2 activation and resulted in more than 80% of phospho-ERK degradation after only 15 min treatment. Moreover,
U0126 had complementary effect on
17-AAG regulated oncogenic and cell cycle related
proteins. Although
17-AAG downregulated
cyclin D1,
cyclin E, CDK4 and CDK6, it led to
cyclin A and CDK2 accumulation, which was reversed by the addition of
U0126. Antiproliferation assay showed that combination of
U0126 and
17-AAG resulted in synergistic cytotoxic effect. More importantly,
17-AAG alone only exhibited moderate inhibition of cell migration in vitro, while addition of
U0126 dramatically enhanced the inhibitory effect by 2- to 5-fold. Taken together, these data demonstrate that
MEK inhibitor
U0126 potentiates the activity of Hsp90 inhibitor
17-AAG against
pancreatic cancer cells. The combination of Hsp90 and
MEK inhibition could provide a promising avenue for the treatment of
pancreatic cancer.