Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors

Hongbo Zhu, Lidong Zhang, Fengqin Dong, Wei Guo, Shuhong Wu, Fuminori Teranishi, John J. Davis, Paul J. Chiao, Bingliang Fang

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Proteasome inhibitors have emerged as promising anticancer therapeutic agents. Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antitumor activity against a wide range of malignancies and has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. However, the molecular mechanisms of bortezomib-mediated apoptosis remain unclear. To characterize the mechanisms of apoptosis induction by proteasome inhibitors, we examined levels of Bcl-2 protein family members (Bik/NBK, Bax, Bak, Bcl-2, and Bcl-XL), release of cytochrome c, and activation of caspase-9 and -3 in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human lung cancer cell line H1299; and human ovarian cancer cell line SKOV3 after they were treated with bortezomib. The result showed that bortezomib induced rapid accumulation of Bik/NBK but not other Bcl-2 family members in all six cell lines. Bortezomib-mediated Bik/NBK accumulation and apoptosis were also observed in human embryonic kidney cells 293 and normal human bronchial epithelial cells. Moreover, dramatic Bik/NBK accumulation and apoptosis induction were observed when cells were treated with proteasome inhibitor MG132 and calpain inhibitor I (ALLN). Furthermore, no detectable changes in IκBα levels or in NFκB functionality were found after treatment with bortezomib. Finally, Bik/NBK accumulation was caused by stabilization of the protein from degradation and was associated with bortezomib cytotoxicity and apoptosis induction. Pretreatment of DLD1 cells with Bik/NBK siRNA reduced bortezomib-mediated Bik/NBK accumulation and cell death. Our results suggested that Bik/NBK is one of the mediators of proteasome inhibitor-induced apoptosis.

Original languageEnglish
Pages (from-to)4993-4999
Number of pages7
JournalOncogene
Volume24
Issue number31
DOIs
Publication statusPublished - Jul 21 2005
Externally publishedYes

Fingerprint

Proteasome Inhibitors
Apoptosis
Cell Line
Bortezomib
Caspase 9
United States Food and Drug Administration
Cytochromes c
Multiple Myeloma
Caspase 3
Antineoplastic Agents
Ovarian Neoplasms
Colonic Neoplasms
Small Interfering RNA
Proteolysis
Lung Neoplasms
Cell Death
Epithelial Cells
Kidney

Keywords

  • Apoptosis
  • Bik
  • Bortezomib
  • Proteasome inhibitor
  • PS-341

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. / Zhu, Hongbo; Zhang, Lidong; Dong, Fengqin; Guo, Wei; Wu, Shuhong; Teranishi, Fuminori; Davis, John J.; Chiao, Paul J.; Fang, Bingliang.

In: Oncogene, Vol. 24, No. 31, 21.07.2005, p. 4993-4999.

Research output: Contribution to journalArticle

Zhu, Hongbo ; Zhang, Lidong ; Dong, Fengqin ; Guo, Wei ; Wu, Shuhong ; Teranishi, Fuminori ; Davis, John J. ; Chiao, Paul J. ; Fang, Bingliang. / Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. In: Oncogene. 2005 ; Vol. 24, No. 31. pp. 4993-4999.
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abstract = "Proteasome inhibitors have emerged as promising anticancer therapeutic agents. Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antitumor activity against a wide range of malignancies and has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. However, the molecular mechanisms of bortezomib-mediated apoptosis remain unclear. To characterize the mechanisms of apoptosis induction by proteasome inhibitors, we examined levels of Bcl-2 protein family members (Bik/NBK, Bax, Bak, Bcl-2, and Bcl-XL), release of cytochrome c, and activation of caspase-9 and -3 in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human lung cancer cell line H1299; and human ovarian cancer cell line SKOV3 after they were treated with bortezomib. The result showed that bortezomib induced rapid accumulation of Bik/NBK but not other Bcl-2 family members in all six cell lines. Bortezomib-mediated Bik/NBK accumulation and apoptosis were also observed in human embryonic kidney cells 293 and normal human bronchial epithelial cells. Moreover, dramatic Bik/NBK accumulation and apoptosis induction were observed when cells were treated with proteasome inhibitor MG132 and calpain inhibitor I (ALLN). Furthermore, no detectable changes in IκBα levels or in NFκB functionality were found after treatment with bortezomib. Finally, Bik/NBK accumulation was caused by stabilization of the protein from degradation and was associated with bortezomib cytotoxicity and apoptosis induction. Pretreatment of DLD1 cells with Bik/NBK siRNA reduced bortezomib-mediated Bik/NBK accumulation and cell death. Our results suggested that Bik/NBK is one of the mediators of proteasome inhibitor-induced apoptosis.",
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AU - Zhu, Hongbo

AU - Zhang, Lidong

AU - Dong, Fengqin

AU - Guo, Wei

AU - Wu, Shuhong

AU - Teranishi, Fuminori

AU - Davis, John J.

AU - Chiao, Paul J.

AU - Fang, Bingliang

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