title: Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD.
abstract: Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that mainly targets vascular endothelial growth factor receptors (VEGFRs). Very recently, sunitinib has been shown to be an active agent for the treatment of malignant pheochromocytomas. However, it is unclear whether sunitinib acts only through an antiangiogenic mechanism or whether it may also directly target tumor cells. Sunitinib markedly induced apoptosis of PC12 cells in a dose-dependent and time-dependent manner. Furthermore, in support of these findings, we found that sunitinib induced a reduction in the expression of the antiapoptotic molecule Bcl-2 as well as dephosphorylation of the proapoptotic molecule BAD, which results in the activation of BAD in these cells. Consistent with these apoptotic effects, our results showed that sunitinib inhibited phosphorylation of Akt and mTOR and was followed by a reduction of S6K1, which is a well-known target of mTOR. Knockdown of VEGFR-2 attenuated the sunitinib-induced effects, including apoptosis and inhibition of signaling pathways such as the phosphorylation of Akt as well as mTOR, and Bcl-2, which confirmed that these effects could be mediated by VEGFR-2. In addition, silencing of S6K1 induced apoptosis accompanied by a decrease in the phosphorylation of BAD and Bcl-2, similar to that observed with sunitinib treatment. Thus, these results together suggest that sunitinib initially exerts its apoptotic effect through the inhibition of VEGFR-2, which, when followed by reduction of its downstream effectors, including Akt/mTOR/S6K1, may lead to inhibition of the antiapoptotic molecule Bcl-2 and activation of the proapoptotic molecule BAD in PC12 cells. However, PC12 cells do not precisely reflect the pathogenesis of malignant cells. Therefore, we confirmed the key findings by replicating these experiments in human neuroblastoma SK-N-SH cells.
authors: Department of Laboratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tskuba, Ibaraki, Japan.
authors: Yuria
authors: Y
authors: Saito
authors: Yuko
authors: Y
authors: Tanaka
authors: Yuichi
authors: Y
authors: Aita
authors: Kiyo-Aki
authors: KA
authors: Ishii
authors: Tatsuhiko
authors: T
authors: Ikeda
authors: Kazumasa
authors: K
authors: Isobe
authors: Yasushi
authors: Y
authors: Kawakami
authors: Hitoshi
authors: H
authors: Shimano
authors: Hisato
authors: H
authors: Hara
authors: Kazuhiro
authors: K
authors: Takekoshi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004396:Coloring Agents; D020287:In Situ Nick-End Labeling; D007202:Indicators and Reagents; D007211:Indoles / Q000494:pharmacology*; D046228:Microarray Analysis; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors*; D016716:PC12 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013778:Tetrazolium Salts; D013844:Thiazoles; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D051025:bcl-Associated Death Protein / Q000187:drug effects / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000964:Antimetabolites, Antineoplastic; C494821:Bad protein, rat; D004396:Coloring Agents; D007202:Indicators and Reagents; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D013844:Thiazoles; D051025:bcl-Associated Death Protein; C546845:mTOR protein, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D051058:Oncogene Protein v-akt; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases; C022616:thiazolyl blue; D001973:Bromodeoxyuridine; D000077210:Sunitinib