Inhibition of Autophagy Enhances Sunitinib-Induced Cytotoxicity in Rat Pheochromocytoma PC12 cells

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Author(s)

    • Ishii Kiyo-aki ISHII Kiyo-aki
    • Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba
    • MIURA Masahiro
    • Department of Laboratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba
    • OTAGIRI Aoi
    • Department of Endocrine Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba
    • KAWAKAMI Yasushi
    • Department of Laboratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba
    • SHIMANO Hitoshi
    • Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba
    • HARA Hisato
    • Department of Endocrine Surgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba
    • TAKEKOSHI Kazuhiro
    • Department of Laboratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba

Abstract

Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity that mainly targets vascular endothelial growth factor receptors, and recently, it has been shown to be an active agent for the treatment of malignant pheochromocytomas. Previously, we demonstrated that sunitinib directly inhibited mTORC1 signaling in rat pheochromocytoma PC12 cells. Although autophagy is a highly regulated cellular process, its relevance to cancer seems to be complicated. It is of note that inhibition of mTORC1 is a prerequisite for autophagy induction. Indeed, direct mTORC1 inhibition initiates ULK1/2 autophosphorylation and subsequent Atg13 and FIP200 phosphorylation, inducing autophagy. Here, we demonstrated that sunitinib significantly increased the levels of LC3-II, concomitant with a decrease of p62 in PC12 cells. Following sunitinib treatment, immunofluorescent imaging revealed a marked increased punctate LC3-II distribution. Furthermore, <i>Atg13</i> knockdown significantly reduced its protein level, which in turn abolished sunitinib-induced autophagy. Moreover, inhibition of autophagy by siRNAs targeting <i>Atg13</i> or by pharmacological inhibition with ammonium chloride, enhanced both sunitinib-induced apoptosis and anti-proliferation. Thus, sunitinib-induced autophagy is dependent on the suppression of mTORC1 signaling and the formation of ULK1/2–Atg13–FIP200 complexes. Inhibition of autophagy may be a promising therapeutic option for improving the anti-tumor effect of sunitinib.

Journal

  • Journal of Pharmacological Sciences

    Journal of Pharmacological Sciences 121(1), 67-73, 2013-01-20

    The Japanese Pharmacological Society

References:  23

Codes

  • NII Article ID (NAID)
    10031147588
  • NII NACSIS-CAT ID (NCID)
    AA11806667
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    13478613
  • NDL Article ID
    024212648
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  NDL  J-STAGE 
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