PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis

Yi He Ling, Leonard Liebes, Bruce Ng, Michael Buckley, Peter J. Elliott, Julian Adams, Jian Dong Jiang, Franco M. Muggia, Roman Perez-Soler

Research output: Contribution to journalArticle

171 Citations (Scopus)

Abstract

Treatment with the proteasome inhibitor, PS-341 resulted in concentration- and time-dependent effects on Bcl-2 phosphorylation and cleavage in H460 cells that coincided with the PS-341-induced G2-M phase arrest. The observed Bcl-2 cleavage paralleled the degree of PS-341-induced apoptosis but was detected to a similar extent with comparable concentrations of two other proteasome inhibitors (MG-132 and PSI). Calpain inhibitors, ALLM and ALLN, and the caspase inhibitors, Z-VAD and AC-YVAD did not induce Bcl-2 phosphorylation and cleavage. Exposure to PS-341 resulted in an additional Mr 25,000 cleavage fragment of Bcl-2, whereas only a Mr 23,000 fragment was observed with other anticancer agents. The formation of the Mr 25,000 fragment was not prevented by caspase inhibitors unlike the Mr 23,000 fragment, which suggests mediation by a caspase-independent pathway. Cell fractionation studies revealed that the Bcl-2 cleaved fragments localize within membrane structures and was an early event (at ∼12 h, posttreatment), and before the observed cleavage of poly(ADP-ribose) polymerase (PARP), β-catenin, and DNA fragmentation (at ∼36 h posttreatment). The Mr 23,000 Bcl-2 cleavage product was inhibited by the pan-caspase inhibitor and the inhibitors of capase-3, -8, -9; but the PARP cleavage was prevented only by the pan-caspase and caspase-3 inhibitors, which suggests that the Mr 23,000 Bcl-2 cleavage occurred at both the initiation and execution stages of apoptosis. The inhibition of the ubiquitin/proteasome pathway by PS-341 leads, at an early stage of apoptosis, to Bcl-2 phosphorylation and a unique proteolytic cleavage product, which are associated with G2-M phase arrest and the induction of apoptosis.

Original languageEnglish (US)
Pages (from-to)841-849
Number of pages9
JournalMolecular Cancer Therapeutics
Volume1
Issue number10
StatePublished - Aug 2002

Fingerprint

Proteasome Inhibitors
G2 Phase
Caspase Inhibitors
Cell Division
Phosphorylation
Apoptosis
Poly(ADP-ribose) Polymerases
Caspases
Cell Fractionation
Catenins
DNA Fragmentation
Proteasome Endopeptidase Complex
Ubiquitin
Caspase 3
Antineoplastic Agents
Bortezomib
Membranes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. / Ling, Yi He; Liebes, Leonard; Ng, Bruce; Buckley, Michael; Elliott, Peter J.; Adams, Julian; Jiang, Jian Dong; Muggia, Franco M.; Perez-Soler, Roman.

In: Molecular Cancer Therapeutics, Vol. 1, No. 10, 08.2002, p. 841-849.

Research output: Contribution to journalArticle

Ling, YH, Liebes, L, Ng, B, Buckley, M, Elliott, PJ, Adams, J, Jiang, JD, Muggia, FM & Perez-Soler, R 2002, 'PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis', Molecular Cancer Therapeutics, vol. 1, no. 10, pp. 841-849.
Ling, Yi He ; Liebes, Leonard ; Ng, Bruce ; Buckley, Michael ; Elliott, Peter J. ; Adams, Julian ; Jiang, Jian Dong ; Muggia, Franco M. ; Perez-Soler, Roman. / PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. In: Molecular Cancer Therapeutics. 2002 ; Vol. 1, No. 10. pp. 841-849.
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T1 - PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis

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AU - Buckley, Michael

AU - Elliott, Peter J.

AU - Adams, Julian

AU - Jiang, Jian Dong

AU - Muggia, Franco M.

AU - Perez-Soler, Roman

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