Mechanisms of proteasome inhibitor PS-341-induced G2-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines

Yi He Ling, Leonard Liebes, Jian Dong Jiang, James F. Holland, Peter J. Elliott, Julian Adams, Franco M. Muggia, Roman Perez-Soler

Research output: Contribution to journalArticle

243 Scopus citations

Abstract

Purpose: PS-341 is a novel dipeptide boronic acid proteasome inhibitor with in vitro and in vivo antitumor activity that induces mechanisms of apoptosis by unknown mechanisms. Experimental Design: Human non-small cell lung cancer cell lines were used to investigate effects PS-341 on cell proliferation, cell cycle progression, and the induction of apoptosis. Results: PS-341 was 38-360-fold more cytotoxic against H460 cells when compared with the proteasome inhibitors MG-132 and PSI. Differential PS-341 cytotoxic effects were found with respect to P53 function: H322 cells (p53 mutant) were 6-fold less sensitive as compared with H460 cells (p53 wild type); and H358 cells (p53 null) were 1.6-fold more sensitive as compared with H460 cells (p53 wild type). A concentration- and time-dependent cell cycle blockade at G2-M phase was seen for H460 cells without any direct effects on microtubule polymerization or depolymerization. PS-341 exposure in H460 cells led to stabilization of p53, induction of p21cip/waf-1 and MDM2 expression, an increase in cyclin B and cyclin A, and the activation of cyclin B and cyclin A kinases. MDM2 induction was found only in H460 cells, whereas in H322 and H358 cells, G2-M-phase arrest, p21cip/waf-1 induction, and an increase in cyclin B1 were found. The commitment of G2-M-phase cells to apoptosis was verified by the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in drug-free medium. Conclusions: Our data suggest that the PS-341-induced G2-M-phase arrest may be associated with the inhibition of degradation of cell cycle regulators and that the up-regulation of p21cip/waf-1 expression may be via p53-dependent and/or -independent pathways. The resulting disturbance of cell cycle progression leads either to growth inhibition or to the initiation of apoptotic pathways.

Original languageEnglish (US)
Pages (from-to)1145-1154
Number of pages10
JournalClinical Cancer Research
Volume9
Issue number3
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ling, Y. H., Liebes, L., Jiang, J. D., Holland, J. F., Elliott, P. J., Adams, J., Muggia, F. M., & Perez-Soler, R. (2003). Mechanisms of proteasome inhibitor PS-341-induced G2-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clinical Cancer Research, 9(3), 1145-1154.