The currently curative therapy for pancreatic endocrine tumours (PET), accounting for <3% of pancreatic tumors, is complete surgical resection, which is achieved in the minority of cases. Most tumors are diagnosed in a late stage, especially in endocrine-inactive forms, indicating the need for further medical therapy. The serinethreonine protein kinase C (PKC) family plays central regulatory roles in several cellular processes, including cell proliferation. PKC signaling and PI3 kinase/Akt pathway, targets of several PKC inhibitors, have been indicated as the most dysregulated in PET, suggesting a possible application for PKC inhibitors in medical therapy of unresectable disease. We aimed to investigate the antiproliferative and antisecretory effects of a novel PKC inhibitor (PI) in the human pancreatic endocrine cancer cell line, BON1, and in a group of six human PET in primary culture. Cell viability was investigated by ATPlite kit, apoptosis by caspase 3/7 assay, GSK3-β phosphorylation and chromogranin A (CgA) secretion by ELISA, PKCβII localization by immunofluorescence, CgA expression by western blot. We found that PI suppresses cell proliferation by inducing apoptosis, and reduces phosphorylation of GSK3-β (Ser9), a downstream target of PKC pathway and a pharmacodynamic marker for PIs. Moreover, treatment with the compound induces translocation of PKCβII from the cytoplasm to the nucleus, and reduces CgA expression and secretion. These data support the hypothesis that the compound reduces cell viability by inducing apoptosis, with a mechanism likely involving GSK3β signaling. In addition, PI inhibits BON1 secretory activity, suggesting that PIs might represent a possible medical treatment of human pancreatic neuroendocrine tumors.
30 Apr - 04 May 2011
European Society of Endocrinology