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

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

References

  • Adams J . (2002a). Oncologist, 7, 9–16.

  • Adams J . (2002b). Curr. Opin. Oncol., 14, 628–634.

  • Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S and Elliott PJ . (1999). Cancer Res., 59, 2615–2622.

  • Boyd JM, Gallo GJ, Elangovan B, Houghton AB, Malstrom S, Avery BJ, Ebb RG, Subramanian T, Chittenden T, Lutz RJ and Chinnadurai, G . (1995). Oncogene, 11, 1921–1928.

  • Gillissen B, Essmann F, Graupner V, Starck L, Radetzki S, Dorken B, Schulze-Osthoff K and Daniel PT . (2003). EMBO J., 22, 3580–3590.

  • Goldstein JC, Waterhouse NJ, Juin P, Evan GI and Green DR . (2000). Nat. Cell Biol., 2, 156–162.

  • Hur J, Chesnes J, Coser KR, Lee RS, Geck P, Isselbacher KJ and Shioda T . (2004). Proc. Natl. Acad. Sci. USA, 101, 2351–2356.

  • Kagawa S, He C, Gu J, Koch P, Rha SJ, Roth JA, Curley SA, Stephens LC and Fang B . (2001). Cancer Res., 61, 3330–3338.

  • Kim GY, Mercer SE, Ewton DZ, Yan Z, Jin K and Friedman E . (2002). J. Biol. Chem., 277, 29792–29802.

  • King RW, Deshaies RJ, Peters JM and Kirschner MW . (1996). Science, 274, 1652–1659.

  • Lara Jr PN, Davies AM, Mack PC, Mortenson MM, Bold RJ, Gumerlock PH and Gandara DR . (2004). Semin. Oncol., 31, 40–46.

  • Lenz HJ . (2003). Cancer Treat. Rev., 29 (Suppl 1), 41–48.

  • Li B and Dou QP . (2000). Proc. Natl. Acad. Sci. USA, 97, 3850–3855.

  • Lin YC, Brown K and Siebenlist U . (1995). Proc. Natl. Acad. Sci. USA, 92, 552–556.

  • Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF and Rolfe M . (1995). Science, 269, 682–685.

  • Palombella VJ, Rando OJ, Goldberg AL and Maniatis T . (1994). Cell, 78, 773–785.

  • Pei XY, Dai Y and Grant S . (2003). Leukemia, 17, 2036–2045.

  • Schmidt C, Peng B, Li Z, Sclabas GM, Fujioka S, Niu J, Schmidt-Supprian M, Evans DB, Abbruzzese JL and Chiao PJ . (2003). Mol. Cell, 12, 1287–1300.

  • Shimizu S and Tsujimoto Y . (2000). Proc. Natl. Acad. Sci. USA, 97, 577–582.

  • Wu S, Zhu H, Gu J, Zhang L, Teraishi F, Davis JJ, Jacob DA and Fang B . (2003). Cancer Res., 64, 1110–1113.

  • Yu J, Tiwari S, Steiner P and Zhang L . (2003). Cancer Biol. Ther., 2, 694–699.

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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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Correspondence to Bingliang Fang.

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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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