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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Abbreviations
- ALLN:
-
calpain inhibitor I
- DMSO:
-
dimethylsulfoxide
- PBS:
-
phosphate-buffered saline
- PMSF:
-
phenylmethylsulfonyl fluoride
- XTT:
-
3-bis-(2-methoxy-4-nitro-5-sulfenyl)-(2H)-tetrazolium-5-carboxanilide
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Acknowledgements
We thank Elizabeth L Hess for editorial review and Alma J Vega for assistance in preparing the manuscript. This article represents partial fulfillment of the requirements for a PhD degree for JJ Davis. This work was supported by National Cancer Institute grants RO1 CA 092487-01A1 (to B Fang), RO1 CA 098582-01A1 (to B Fang), CA-16672, and the Lockton grant-matching fund.
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Zhu, H., Zhang, L., Dong, F. et al. Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. Oncogene 24, 4993–4999 (2005). https://doi.org/10.1038/sj.onc.1208683
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DOI: https://doi.org/10.1038/sj.onc.1208683
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