Inhibition of proteasome activity by bortezomib in renal cancer cells is p53 dependent and VHL independent

Susan A J Vaziri, Dale R. Grabowski, Jason Hill, Lisa R. Rybicki, Robert D. Burk, Ronald M. Bukowski, Mahrukh K. Ganapathi, Ram Ganapathi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background: Antiproliferative effects of proteasome inhibitors are suggested to be primarily due to effects on nuclear factor-κB (NF-κB)-dependent pathways and the induction of apoptosis. The objective of this study was to elucidate the mechanistic basis for the antiproliferative effects of the proteasome inhibitor, bortezomib, in human clear cell renal cell cancer cells (CCRCC). Materials and Methods: von Hippel Lindau (VHL) mutation/methylation status and cytotoxic response to bortezomib was determined in a panel of CCRCC cell lines. Effects on target protein/gene expression and the role of p53 in bortezomib-mediated cytotoxicity, inhibition of proteasome activity, survivin transcript and protein expression as well as induction of p21 expression was determined in CCRCC that differed in their intrinsic sensitivity to bortezomib. Results: VHL status was not associated with cytotoxic response to bortezomib treatment. Cytotoxicity in cell lines that differed in intrinsic sensitivity to bortezomib correlated with sustained inhibition of proteasome activity, survivin expression and induction of p21 expression. Stable down-regulation of p53 expression by siRNA led to attenuation of bortezomib effects, survivin down-regulation and p21 induction, suggesting that cellular effects are p53-dependent. Conclusion: These results demonstrate that the antiproliferative effects of bortezomib in CCRCC cells are VHL independent and dependent on pathways regulated by p53.

Original languageEnglish (US)
Pages (from-to)2961-2969
Number of pages9
JournalAnticancer Research
Volume29
Issue number8
StatePublished - Aug 2009

Fingerprint

Proteasome Endopeptidase Complex
Renal Cell Carcinoma
Proteasome Inhibitors
Down-Regulation
Bortezomib
Cell Line
Methylation
Small Interfering RNA
Proteins
Apoptosis
Gene Expression
Mutation

Keywords

  • Bortezomib
  • p53
  • Proteasome
  • Renal cancer
  • VHL

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Vaziri, S. A. J., Grabowski, D. R., Hill, J., Rybicki, L. R., Burk, R. D., Bukowski, R. M., ... Ganapathi, R. (2009). Inhibition of proteasome activity by bortezomib in renal cancer cells is p53 dependent and VHL independent. Anticancer Research, 29(8), 2961-2969.

Inhibition of proteasome activity by bortezomib in renal cancer cells is p53 dependent and VHL independent. / Vaziri, Susan A J; Grabowski, Dale R.; Hill, Jason; Rybicki, Lisa R.; Burk, Robert D.; Bukowski, Ronald M.; Ganapathi, Mahrukh K.; Ganapathi, Ram.

In: Anticancer Research, Vol. 29, No. 8, 08.2009, p. 2961-2969.

Research output: Contribution to journalArticle

Vaziri, SAJ, Grabowski, DR, Hill, J, Rybicki, LR, Burk, RD, Bukowski, RM, Ganapathi, MK & Ganapathi, R 2009, 'Inhibition of proteasome activity by bortezomib in renal cancer cells is p53 dependent and VHL independent', Anticancer Research, vol. 29, no. 8, pp. 2961-2969.
Vaziri SAJ, Grabowski DR, Hill J, Rybicki LR, Burk RD, Bukowski RM et al. Inhibition of proteasome activity by bortezomib in renal cancer cells is p53 dependent and VHL independent. Anticancer Research. 2009 Aug;29(8):2961-2969.
Vaziri, Susan A J ; Grabowski, Dale R. ; Hill, Jason ; Rybicki, Lisa R. ; Burk, Robert D. ; Bukowski, Ronald M. ; Ganapathi, Mahrukh K. ; Ganapathi, Ram. / Inhibition of proteasome activity by bortezomib in renal cancer cells is p53 dependent and VHL independent. In: Anticancer Research. 2009 ; Vol. 29, No. 8. pp. 2961-2969.
@article{b6fe33c4da9c4949be040e722464835b,
title = "Inhibition of proteasome activity by bortezomib in renal cancer cells is p53 dependent and VHL independent",
abstract = "Background: Antiproliferative effects of proteasome inhibitors are suggested to be primarily due to effects on nuclear factor-κB (NF-κB)-dependent pathways and the induction of apoptosis. The objective of this study was to elucidate the mechanistic basis for the antiproliferative effects of the proteasome inhibitor, bortezomib, in human clear cell renal cell cancer cells (CCRCC). Materials and Methods: von Hippel Lindau (VHL) mutation/methylation status and cytotoxic response to bortezomib was determined in a panel of CCRCC cell lines. Effects on target protein/gene expression and the role of p53 in bortezomib-mediated cytotoxicity, inhibition of proteasome activity, survivin transcript and protein expression as well as induction of p21 expression was determined in CCRCC that differed in their intrinsic sensitivity to bortezomib. Results: VHL status was not associated with cytotoxic response to bortezomib treatment. Cytotoxicity in cell lines that differed in intrinsic sensitivity to bortezomib correlated with sustained inhibition of proteasome activity, survivin expression and induction of p21 expression. Stable down-regulation of p53 expression by siRNA led to attenuation of bortezomib effects, survivin down-regulation and p21 induction, suggesting that cellular effects are p53-dependent. Conclusion: These results demonstrate that the antiproliferative effects of bortezomib in CCRCC cells are VHL independent and dependent on pathways regulated by p53.",
keywords = "Bortezomib, p53, Proteasome, Renal cancer, VHL",
author = "Vaziri, {Susan A J} and Grabowski, {Dale R.} and Jason Hill and Rybicki, {Lisa R.} and Burk, {Robert D.} and Bukowski, {Ronald M.} and Ganapathi, {Mahrukh K.} and Ram Ganapathi",
year = "2009",
month = "8",
language = "English (US)",
volume = "29",
pages = "2961--2969",
journal = "Anticancer Research",
issn = "0250-7005",
publisher = "International Institute of Anticancer Research",
number = "8",

}

TY - JOUR

T1 - Inhibition of proteasome activity by bortezomib in renal cancer cells is p53 dependent and VHL independent

AU - Vaziri, Susan A J

AU - Grabowski, Dale R.

AU - Hill, Jason

AU - Rybicki, Lisa R.

AU - Burk, Robert D.

AU - Bukowski, Ronald M.

AU - Ganapathi, Mahrukh K.

AU - Ganapathi, Ram

PY - 2009/8

Y1 - 2009/8

N2 - Background: Antiproliferative effects of proteasome inhibitors are suggested to be primarily due to effects on nuclear factor-κB (NF-κB)-dependent pathways and the induction of apoptosis. The objective of this study was to elucidate the mechanistic basis for the antiproliferative effects of the proteasome inhibitor, bortezomib, in human clear cell renal cell cancer cells (CCRCC). Materials and Methods: von Hippel Lindau (VHL) mutation/methylation status and cytotoxic response to bortezomib was determined in a panel of CCRCC cell lines. Effects on target protein/gene expression and the role of p53 in bortezomib-mediated cytotoxicity, inhibition of proteasome activity, survivin transcript and protein expression as well as induction of p21 expression was determined in CCRCC that differed in their intrinsic sensitivity to bortezomib. Results: VHL status was not associated with cytotoxic response to bortezomib treatment. Cytotoxicity in cell lines that differed in intrinsic sensitivity to bortezomib correlated with sustained inhibition of proteasome activity, survivin expression and induction of p21 expression. Stable down-regulation of p53 expression by siRNA led to attenuation of bortezomib effects, survivin down-regulation and p21 induction, suggesting that cellular effects are p53-dependent. Conclusion: These results demonstrate that the antiproliferative effects of bortezomib in CCRCC cells are VHL independent and dependent on pathways regulated by p53.

AB - Background: Antiproliferative effects of proteasome inhibitors are suggested to be primarily due to effects on nuclear factor-κB (NF-κB)-dependent pathways and the induction of apoptosis. The objective of this study was to elucidate the mechanistic basis for the antiproliferative effects of the proteasome inhibitor, bortezomib, in human clear cell renal cell cancer cells (CCRCC). Materials and Methods: von Hippel Lindau (VHL) mutation/methylation status and cytotoxic response to bortezomib was determined in a panel of CCRCC cell lines. Effects on target protein/gene expression and the role of p53 in bortezomib-mediated cytotoxicity, inhibition of proteasome activity, survivin transcript and protein expression as well as induction of p21 expression was determined in CCRCC that differed in their intrinsic sensitivity to bortezomib. Results: VHL status was not associated with cytotoxic response to bortezomib treatment. Cytotoxicity in cell lines that differed in intrinsic sensitivity to bortezomib correlated with sustained inhibition of proteasome activity, survivin expression and induction of p21 expression. Stable down-regulation of p53 expression by siRNA led to attenuation of bortezomib effects, survivin down-regulation and p21 induction, suggesting that cellular effects are p53-dependent. Conclusion: These results demonstrate that the antiproliferative effects of bortezomib in CCRCC cells are VHL independent and dependent on pathways regulated by p53.

KW - Bortezomib

KW - p53

KW - Proteasome

KW - Renal cancer

KW - VHL

UR - http://www.scopus.com/inward/record.url?scp=68549094348&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68549094348&partnerID=8YFLogxK

M3 - Article

C2 - 19661301

AN - SCOPUS:68549094348

VL - 29

SP - 2961

EP - 2969

JO - Anticancer Research

JF - Anticancer Research

SN - 0250-7005

IS - 8

ER -