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

Sjölund, Jonas LU ; Johansson, Martin LU ; Manna, Sugata LU ; Norin, Carl; Pietras, Alexander LU ; Beckman, Siv LU ; Nilsson, Elise LU ; Ljungberg, Börje and Axelson, Håkan LU (2008) In Journal of Clinical Investigation 118(1). p.217-228
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Investigation
volume
118
issue
1
pages
217 - 228
publisher
The Journal of Clinical Investigation
external identifiers
  • pmid:18079963
  • wos:000252122900023
  • scopus:38149015554
ISSN
0021-9738
DOI
10.1172/JCI32086
language
English
LU publication?
yes
id
1c1eac32-f2e0-4bf0-9691-4d1b26796d63 (old id 949732)
alternative location
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2129233
date added to LUP
2008-09-12 11:04:23
date last changed
2017-10-22 03:59:35
@article{1c1eac32-f2e0-4bf0-9691-4d1b26796d63,
  abstract     = {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.},
  author       = {Sjölund, Jonas and Johansson, Martin and Manna, Sugata and Norin, Carl and Pietras, Alexander and Beckman, Siv and Nilsson, Elise and Ljungberg, Börje and Axelson, Håkan},
  issn         = {0021-9738},
  language     = {eng},
  number       = {1},
  pages        = {217--228},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo},
  url          = {http://dx.doi.org/10.1172/JCI32086},
  volume       = {118},
  year         = {2008},
}