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Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo

Author:
  • Jonas Sjölund
  • Martin Johansson
  • Sugata Manna
  • Carl Norin
  • Alexander Pietras
  • Siv Beckman
  • Elise Nilsson
  • Börje Ljungberg
  • Håkan Axelson
Publishing year: 2008
Language: English
Pages: 217-228
Publication/Series: Journal of Clinical Investigation
Volume: 118
Issue: 1
Document type: Journal article
Publisher: American Society for Clinical Investigation

Abstract english

Loss of the tumor suppressor gene von Hippel–Lindau (VHL) plays a key role in the oncogenesis of clear cell renal cell carcinoma (CCRCC). The loss leads to stabilization of the HIF transcription complex, which induces angiogenic and mitogenic pathways essential for tumor formation. Nonetheless, additional oncogenic events have been postulated to be required for the formation of CCRCC tumors. Here, we show that the Notch signaling cascade is constitutively active in human CCRCC cell lines independently of the VHL/HIF pathway. Blocking Notch signaling resulted in attenuation of proliferation and restrained anchorage-independent growth of CCRCC cell lines. Using siRNA targeting the different Notch receptors established that the growth-promoting effects of the Notch signaling pathway were attributable to Notch-1 and that Notch-1 knockdown was accompanied by elevated levels of the negative cell-cycle regulators p21Cip1 and/or p27Kip1. Treatment of nude mice with an inhibitor of Notch signaling potently inhibited growth of xenotransplanted CCRCC cells. Moreover, Notch-1 and the Notch ligand Jagged-1 were expressed at significantly higher levels in CCRCC tumors than in normal human renal tissue, and the growth of primary CCRCC cells was attenuated upon inhibition of Notch signaling. These findings indicate that the Notch cascade may represent a novel and therapeutically accessible pathway in CCRCC.

Keywords

  • Cancer and Oncology

Other

Published
  • Pathology, Malmö
  • Kidney cancer research group
  • ISSN: 0021-9738
Håkan Axelson
E-mail: hakan.axelson [at] med.lu.se

Professor

Division of Translational Cancer Research

+46 46 222 64 34

MV 404 A31A2

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