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Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM)

Oncogene volume 24, pages 344–354 (2005)Cite this article

Abstract

The proteasome plays a pivotal role in controlling cell proliferation, apoptosis, and differentiation in a variety of normal and tumor cells. PS-341, a novel boronic acid dipeptide that inhibits 26S proteasome activity, has prominent effects in vitro and in vivo against several solid tumors. We examined its antiproliferation, proapoptotic effects using three human glioblastoma multiforme (GBM) cell lines and five primary GBM explants. PS-341 markedly inhibited proliferation of GBM cell lines and explants in liquid and soft agar culture. These cells developed a G2/M cell cycle arrest with a concomitant decreased percentage of cells in S phase (≈2-fold), associated with an increased expression of p21WAF1, p27KIP1, as well as cyclin B1 and decreased levels of CDK2, CDK4, and E2F4. About 35–40% of the cells became apoptotic when exposed to PS-341 (10−7 M, 24–48 h) as shown by Annexin V analysis; in concert with these findings, immunobloting showed a C-terminal 85 kDa apoptotic fragment of poly ADP-ribose polymerase (PARP), and a decreased level of Bcl2 and Bcl-xl. PS-341 downregulated the expression of Bcl-2 and Bcl-xl in protein levels at an early time of treatment. These changes occurred irrespective of the p53 mutational status of the cells. PS-341 activated JNK/c-Jun signaling in GBM cells, and the JNK inhibitor SP600125 blocked the JNK signaling to reverse partially the PS-341 growth inhibition. PS-341 (10−7 M, 24 h) decreased nuclear NF-κB levels as shown by Western blot, and reduced transcriptional activity of NF-κB as measured by reporter assays in these transformed cells. Also, PS-341 enhanced TRAIL (TNF-related apoptosis-inducing ligand) and TNFα (tumor necrosis factor alpha) induced cell death and apoptosis (two- to five-fold) in GBM cells. In summary, PS-341 has profound effects on growth and apoptosis of GBM cells, suggesting that PS-341 may be an effective therapy for patients with gliomas.

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Abbreviations

GBM:

glioblastoma multiforme

SSCP:

single-strand conformation polymorphism

PARP:

poly ADP-ribose polymerase

MM:

mutiple myeloma

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

TNFα:

tumor necrosis factor alpha

TRAIL:

TNF-related apoptosis-inducing ligand

wt:

wild type

mt:

mutant

PS-341:

Velcade/bortezomib

PI:

propidium iodide

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Acknowledgements

This work was supported in part by National Institutes of Health, Ko-So Foundation, Parker Hughes Trust, and the Inger Fund, as well as a grant from the Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center. HPK is a member of the Molecular Biology Institute and Jonsson Comprehensive Cancer Center at UCLA, and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine. This work is in loving memory of Matt Shreck.

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  1. Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, 90048, USA

    Dong Yin, Hong Zhou, Takashi Kumagai & H Phillip Koeffler

  2. Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, 90048, USA

    Gentao Liu, John M Ong & Keith L Black

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  1. Dong Yin
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Correspondence to Dong Yin.

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Yin, D., Zhou, H., Kumagai, T. et al. Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene 24, 344–354 (2005). https://doi.org/10.1038/sj.onc.1208225

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