Sunitinib Inhibits Catecholamine Synthesis and Secretion in Pheochromocytoma Tumor Cells by Blocking VEGF Receptor 2 via PLC-γ-related Pathways

Sunitinib is an oral, small molecule multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that primarily targets vascular endothelial growth factor receptors (VEGFRs). Although sunitinib is an active agent for the treatment of malignant pheochromocytomas, it is unclear whether sunitinib acts through only antiangiogenic mechanisms or also directly targets tumor cells. We previously showed that sunitinib directly induced apoptosis of PC-12 cells. To further confirm these direct effects, we examined the effects of sunitinib on tyrosine hydroxylase (TH) (the rate-limiting enzyme in catecholamine biosynthesis) activity and catecholamine secretion in PC-12 cells and the underlying mechanisms. Sunitinib inhibited TH activity in a dose-dependent manner, and decreased TH protein levels. Consistent with this finding, sunitinib decreased TH phosphorylation at Ser31 and Ser40 and significantly decreased catecholamine secretion. VEGFR-2 knockdown attenuated these effects, includi...