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Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma.

Publication ,  Journal Article
Yang, DT; Young, KH; Kahl, BS; Markovina, S; Miyamoto, S
Published in: Mol Cancer
May 19, 2008

BACKGROUND: The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-kappaB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL). However, NF-kappaB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-kappaB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear. RESULTS: Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-kappaB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA). Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231) and a breast carcinoma cell line (MDA-MB-468), the bortezomib-resistant NF-kappaB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10) displayed bortezomib-resistant constitutive NF-kappaB activity. CONCLUSION: Our findings show that bortezomib-resistant NF-kappaB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.

Duke Scholars

Published In

Mol Cancer

DOI

EISSN

1476-4598

Publication Date

May 19, 2008

Volume

7

Start / End Page

40

Location

England

Related Subject Headings

  • Pyrazines
  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex
  • Oncology & Carcinogenesis
  • NF-kappa B
  • Middle Aged
  • Male
  • Lymphoma, Mantle-Cell
  • Humans
  • Female
 

Citation

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Yang, D. T., Young, K. H., Kahl, B. S., Markovina, S., & Miyamoto, S. (2008). Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma. Mol Cancer, 7, 40. https://doi.org/10.1186/1476-4598-7-40
Yang, David T., Ken H. Young, Brad S. Kahl, Stephanie Markovina, and Shigeki Miyamoto. “Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma.Mol Cancer 7 (May 19, 2008): 40. https://doi.org/10.1186/1476-4598-7-40.
Yang DT, Young KH, Kahl BS, Markovina S, Miyamoto S. Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma. Mol Cancer. 2008 May 19;7:40.
Yang, David T., et al. “Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma.Mol Cancer, vol. 7, May 2008, p. 40. Pubmed, doi:10.1186/1476-4598-7-40.
Yang DT, Young KH, Kahl BS, Markovina S, Miyamoto S. Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma. Mol Cancer. 2008 May 19;7:40.
Journal cover image

Published In

Mol Cancer

DOI

EISSN

1476-4598

Publication Date

May 19, 2008

Volume

7

Start / End Page

40

Location

England

Related Subject Headings

  • Pyrazines
  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex
  • Oncology & Carcinogenesis
  • NF-kappa B
  • Middle Aged
  • Male
  • Lymphoma, Mantle-Cell
  • Humans
  • Female