"PKC come nuovo target molecolare nel controllo della proliferazione cellulare dei tumori neuroendocrini"

Abstract

Dysregulation of the protein kinase C (PKC) signaling pathway has been implicated in tumor progression. In this study, we investigate the effects of a PKC inhibitor, Enzastaurin, in human pancreatic neuroendocrine neoplasms (PNN) primary cultures, in BON1 cell line, in human medullary thyroid carcinoma (MTC) primary culture and in TT cell line. We found that PKC inhibition reduces cell proliferation by inducing caspase mediated apoptosis and blocks the stimulatory effects of IGF-I on CT secretion in MTC, and CgA secretion in PNN. Enzastaurin reduces PKCβII(Thr500) phosphorylation, indicating a direct involvement of this isoform as well as phosphirylated levels of Akt(ser473) and GSK3β(Ser9), PKC pathway downstream targets and pharmacodynamic markers for PKC inhibition. PKCβII and PKCδ enzyme isoforms expression and localization were investigated. These data indicate that in vitro PKC is involved in the control of human PNN and human MTC proliferation and survival by modulating apoptosis, with a mechanism that implicates PKCβII inhibition and translocation in different subcellular compartments. In conclusion, targeting PKC may represent a useful therapeutic approach for controlling of neuroendocrine tumors proliferation.