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.