title: FKBP5 as a selection biomarker for gemcitabine and Akt inhibitors in treatment of pancreatic cancer.
abstract: We have recently shown that the immunophilin FKBP5 (also known as FKBP51) is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP-mediated dephosphorylation of Akt Ser473, negatively regulating Akt activation in vitro. Therefore, FKBP5 might function as a tumor suppressor, and levels of FKBP5 would affect cell response to chemotherapy. In the current study, we have taken a step forward by using a pancreatic cancer xenograft mice model to show that down regulation of FKBP5 in shFKBP5 xenograft mice promotes tumor growth and resistance to gemcitabine, a phenomenon consistent with our previous findings in pancreatic cell lines. In addition, we also found that inhibitors targeting the Akt pathway, including PI3K inhibitor, Akt inhibitor and mTOR inhibitor had a different effect on sensitization to gemcitabine and other chemotherapeutic agents in cell lines, with a specific Akt inhibitor, triciribine, having the greatest sensitization effect. We then tested the hypothesis that addition of triciribine can sensitize gemcitabine treatment, especially in shFKBP5 pancreatic cancer xenograft mice. We found that combination treatment with gemcitabine and triciribine has a better effect on tumor inhibition than either drug alone (p<0.005) and that the inhibition effect is more significant in shFKBP5 xenograft mice than wt mice (p<0.05). These effects were correlated with level of Akt 473 phosphorylation as well as proliferation rate, as indicated by Ki67 staining in xenograft tumor tissues. These results provide evidence in support of future clinical trials designed to tailor therapy based on our observations.
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Junmei
authors.initials: J
authors.lastname: Hou
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000093542:Gemcitabine; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D003841:Deoxycytidine; D051057:Proto-Oncogene Proteins c-akt; D012263:Ribonucleosides; D022021:Tacrolimus Binding Proteins; D000093542:Gemcitabine; D000099159:Tacrolimus Binding Protein 5; C023764:triciribine