Invasion, metastasis and resistance to conventional chemotherapeutic agents are obstacles to successful treatment of pancreatic cancer, and a better understanding of the molecular basis of this malignancy may lead to improved therapeutics. In the present study, we investigated whether
AKT2 silencing sensitized pancreatic cancer L3.6pl, BxPC-3, PANC-1 and MIAPaCa-2 cells to gemcitabine
via regulating PUMA (p53-upregulated modulator of apoptosis) and nuclear factor (NF)-κB signaling pathway. MTT, TUNEL, EMSA and
NF-κB reporter assays were used to detect tumor cell proliferation, apoptosis and
NF-κB activity. Western blotting was used to detect different protein levels. Xenograft of established tumors was used to evaluate primary tumor growth and apoptosis after treatment with gemcitabine alone or in combination with
AKT2 siRNA. Gemcitabine activated
AKT2 and
NF-κB in MIAPaCa-2 and L3.6pl cells
in vitro or
in vivo, and in PANC-1 cells only
in vivo. Gemcitabine only activated
NF-κB in BxPC-3 cells
in vitro. The presence of PUMA was necessary for gemcitabine-induced apoptosis only in BxPC-3 cells
in vitro.
AKT2 inhibition sensitized gemcitabine-induced apoptosis via PUMA upregulation in MIAPaCa-2 cells
in vitro, and via
NF-κB activity inhibition in L3.6pl cells
in vitro. In PANC-1 and MIAPaCa-2 cells
in vivo,
AKT2 inhibition sensitized gemcitabine-induced apoptosis and growth inhibition via both PUMA upregulation and
NF-κB inhibition. We suggest that
AKT2 inhibition abrogates gemcitabine-induced activation of
AKT2 and
NF-κB, and promotes gemcitabine-induced PUMA upregulation, resulting in chemosensitization of pancreatic tumors to gemcitabine, which is probably an important strategy for the treatment of pancreatic cancer.
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