Insulin-like Growth Factor I (IGF-I) is a well known stimulator of cell proliferation also in the settings of neuroendocrine tumors. Previous evidence has shown that IGF-I stimulates cell proliferation and resistance to pro-apoptotic stimuli both in human pancreatic endocrine tumor (PET) and in medullary thyroid carcinoma (MTC) cell lines and primary cultures. IGF-I signals through many pathways, including protein kinase C (PKC). We here investigate whether PKC may mediate IGF-I proliferative stimuli in two different in vitro models, represented by PET primary cultures and the BON1 cell line and by MTC primary cultures and the TT cell line, by using a novel PKC inhibitor, Enzastaurin. We found that Enzastaurin inhibits IGF-I stimulated cell proliferation at 5 and 10 µM (concentrations reached also at plasma level in human clinical trials) by inducing caspase-mediated apoptosis both in PET-derived and in MTC-derived cells. We found that Enzastaurin also reduces IGF-I stimulated phosphorylation of glycogen synthetase kinase 3 beta (GSK3-β), a downstream target of PKC pathway and a pharmacodynamic marker for Enzastaurin in BON1 and TT cells. These data indicate that in endocrine tumor cell lines Enzastaurin blocks IGF-I induced proliferative stimuli inducing apoptosis, with a mechanism likely involving GSK3β signaling, indicating that PKC plays a crucial role in the control of human neuroendocrine tumor proliferation and survival and that PKC inhibitors may represent a new pharmacological target in neuroendocrine tumors.
IGF-I Proliferative Effects Are Inhibited by Targeting PKC in Human Endocrine Tumor Cells
MOLE', Daniela;GAGLIANO, Teresa;GENTILIN, Erica;BONDANELLI, Marta;TAGLIATI, Federico;DEGLI UBERTI, Ettore;ZATELLI, Maria Chiara
2011
Abstract
Insulin-like Growth Factor I (IGF-I) is a well known stimulator of cell proliferation also in the settings of neuroendocrine tumors. Previous evidence has shown that IGF-I stimulates cell proliferation and resistance to pro-apoptotic stimuli both in human pancreatic endocrine tumor (PET) and in medullary thyroid carcinoma (MTC) cell lines and primary cultures. IGF-I signals through many pathways, including protein kinase C (PKC). We here investigate whether PKC may mediate IGF-I proliferative stimuli in two different in vitro models, represented by PET primary cultures and the BON1 cell line and by MTC primary cultures and the TT cell line, by using a novel PKC inhibitor, Enzastaurin. We found that Enzastaurin inhibits IGF-I stimulated cell proliferation at 5 and 10 µM (concentrations reached also at plasma level in human clinical trials) by inducing caspase-mediated apoptosis both in PET-derived and in MTC-derived cells. We found that Enzastaurin also reduces IGF-I stimulated phosphorylation of glycogen synthetase kinase 3 beta (GSK3-β), a downstream target of PKC pathway and a pharmacodynamic marker for Enzastaurin in BON1 and TT cells. These data indicate that in endocrine tumor cell lines Enzastaurin blocks IGF-I induced proliferative stimuli inducing apoptosis, with a mechanism likely involving GSK3β signaling, indicating that PKC plays a crucial role in the control of human neuroendocrine tumor proliferation and survival and that PKC inhibitors may represent a new pharmacological target in neuroendocrine tumors.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
