title: MEK inhibition potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, MI 48109, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Zhu
authors.forename: Mancang
authors.initials: M
authors.lastname: Gu
authors.forename: Bryan
authors.initials: B
authors.lastname: Newman
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D016227:Benzoquinones / Q000008:administration & dosage*; D002070:Butadienes / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009570:Nitriles / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D002070:Butadienes; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; C112765:tanespimycin; D019061:src-Family Kinases