Targeting BCL-2 overexpression in various human malignancies through NF-κB inhibition by the proteasome inhibitor bortezomib

Bridget N. Fahy, Michael G. Schlieman, Melinda M. Mortenson, Subbulakshmi Virudachalam, Richard J Bold

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Background: BCL-2 overexpression occurs in many cancer types and is associated with chemoresistance and radioresistance. The mechanisms responsible for its aberrant expression are thought to be transcriptionally mediated but remain unclear. We examined the cell type-specific mechanism of BCL-2 gene transcription in various solid organ malignancies. Methods: Regulation of BCL-2 gene transcription was examined in seven different human cancer cell lines including two pancreatic (MIA-PaCa-2, PANC-1), two prostate (LNCaP, PC-3), two lung (Calu-1, A549) and one breast (MCF-7) cancer cell line. Cells were treated with inhibitors of phosphatidylinositol-3 kinase (PI3K), MEK/ERK, and p38MAPK. The effect of mutation of a NF-κB site in the BCL-2 promoter was determined, as was the effect of inhibition of NF-κB function using a 26S proteasome inhibitor (bortezomib) on both BCL-2 transcription and induction of apoptosis. Results: BCL-2 expression varied both between and within tumor types; four of seven cell lines demonstrated high BCL-2 levels (MIA-PaCa-2, PC-3, Calu-1 and MCF-7). No signaling pathway was uniformly responsible for overexpression of BCL-2; however, mutation of the NF-κB site decreased BCL-2 promoter activity in all cell lines. Inhibition of NF-κB activity decreased BCL-2 protein levels independently of the signaling pathway involved in transcriptional activation of the BCL-2 gene. Conclusions: Diverse signaling pathways variably regulate BCL-2 gene expression in a cell type-specific fashion. Therapy to decrease BCL-2 levels in various human cancers would be more broadly applicable if targeted to transcriptional activation rather than signal transduction cascades. Finally, the apoptotic efficacy of proteasome inhibition with bortezomib paralleled the ability to inhibit NF-κB activity and decrease BCL-2 levels.

Original languageEnglish (US)
Pages (from-to)46-54
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume56
Issue number1
DOIs
StatePublished - Jul 2005

Fingerprint

Proteasome Inhibitors
Transcription
Cells
Genes
Cell Line
Neoplasms
Chemical activation
Phosphatidylinositol 3-Kinase
Signal transduction
Transcriptional Activation
Mitogen-Activated Protein Kinase Kinases
Proteasome Endopeptidase Complex
Gene expression
Tumors
Mutation
MCF-7 Cells
Apoptosis
Bortezomib
Prostate
Signal Transduction

Keywords

  • BCL-2
  • MEK/ERK
  • NF-κB
  • p38MAPK
  • PI-3 Kinase

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Targeting BCL-2 overexpression in various human malignancies through NF-κB inhibition by the proteasome inhibitor bortezomib. / Fahy, Bridget N.; Schlieman, Michael G.; Mortenson, Melinda M.; Virudachalam, Subbulakshmi; Bold, Richard J.

In: Cancer Chemotherapy and Pharmacology, Vol. 56, No. 1, 07.2005, p. 46-54.

Research output: Contribution to journalArticle

Fahy, Bridget N. ; Schlieman, Michael G. ; Mortenson, Melinda M. ; Virudachalam, Subbulakshmi ; Bold, Richard J. / Targeting BCL-2 overexpression in various human malignancies through NF-κB inhibition by the proteasome inhibitor bortezomib. In: Cancer Chemotherapy and Pharmacology. 2005 ; Vol. 56, No. 1. pp. 46-54.
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AU - Virudachalam, Subbulakshmi

AU - Bold, Richard J

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N2 - Background: BCL-2 overexpression occurs in many cancer types and is associated with chemoresistance and radioresistance. The mechanisms responsible for its aberrant expression are thought to be transcriptionally mediated but remain unclear. We examined the cell type-specific mechanism of BCL-2 gene transcription in various solid organ malignancies. Methods: Regulation of BCL-2 gene transcription was examined in seven different human cancer cell lines including two pancreatic (MIA-PaCa-2, PANC-1), two prostate (LNCaP, PC-3), two lung (Calu-1, A549) and one breast (MCF-7) cancer cell line. Cells were treated with inhibitors of phosphatidylinositol-3 kinase (PI3K), MEK/ERK, and p38MAPK. The effect of mutation of a NF-κB site in the BCL-2 promoter was determined, as was the effect of inhibition of NF-κB function using a 26S proteasome inhibitor (bortezomib) on both BCL-2 transcription and induction of apoptosis. Results: BCL-2 expression varied both between and within tumor types; four of seven cell lines demonstrated high BCL-2 levels (MIA-PaCa-2, PC-3, Calu-1 and MCF-7). No signaling pathway was uniformly responsible for overexpression of BCL-2; however, mutation of the NF-κB site decreased BCL-2 promoter activity in all cell lines. Inhibition of NF-κB activity decreased BCL-2 protein levels independently of the signaling pathway involved in transcriptional activation of the BCL-2 gene. Conclusions: Diverse signaling pathways variably regulate BCL-2 gene expression in a cell type-specific fashion. Therapy to decrease BCL-2 levels in various human cancers would be more broadly applicable if targeted to transcriptional activation rather than signal transduction cascades. Finally, the apoptotic efficacy of proteasome inhibition with bortezomib paralleled the ability to inhibit NF-κB activity and decrease BCL-2 levels.

AB - Background: BCL-2 overexpression occurs in many cancer types and is associated with chemoresistance and radioresistance. The mechanisms responsible for its aberrant expression are thought to be transcriptionally mediated but remain unclear. We examined the cell type-specific mechanism of BCL-2 gene transcription in various solid organ malignancies. Methods: Regulation of BCL-2 gene transcription was examined in seven different human cancer cell lines including two pancreatic (MIA-PaCa-2, PANC-1), two prostate (LNCaP, PC-3), two lung (Calu-1, A549) and one breast (MCF-7) cancer cell line. Cells were treated with inhibitors of phosphatidylinositol-3 kinase (PI3K), MEK/ERK, and p38MAPK. The effect of mutation of a NF-κB site in the BCL-2 promoter was determined, as was the effect of inhibition of NF-κB function using a 26S proteasome inhibitor (bortezomib) on both BCL-2 transcription and induction of apoptosis. Results: BCL-2 expression varied both between and within tumor types; four of seven cell lines demonstrated high BCL-2 levels (MIA-PaCa-2, PC-3, Calu-1 and MCF-7). No signaling pathway was uniformly responsible for overexpression of BCL-2; however, mutation of the NF-κB site decreased BCL-2 promoter activity in all cell lines. Inhibition of NF-κB activity decreased BCL-2 protein levels independently of the signaling pathway involved in transcriptional activation of the BCL-2 gene. Conclusions: Diverse signaling pathways variably regulate BCL-2 gene expression in a cell type-specific fashion. Therapy to decrease BCL-2 levels in various human cancers would be more broadly applicable if targeted to transcriptional activation rather than signal transduction cascades. Finally, the apoptotic efficacy of proteasome inhibition with bortezomib paralleled the ability to inhibit NF-κB activity and decrease BCL-2 levels.

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KW - p38MAPK

KW - PI-3 Kinase

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