Molecular characterization of PS-341 (bortezomib) resistance: Implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-β inhibitors

Teru Hideshima, Dharminder Chauhan, Kenji Ishitsuka, Hiroshi Yasui, Noopur Raje, Shaji Kumar, Klaus Podar, Constantine Mitsiades, Hiromasa Hideshima, Lynn Bonham, Nikhil C. Munshi, Paul G. Richardson, Jack W. Singer, Kenneth C. Anderson

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

PS-341 (bortezomib, Velcade™) is a promising novel agent for treatment of advanced multiple myeloma (MM); however, 65% of patients with relapsed refractory disease in a phase II study do not respond to PS-341. We have previously shown that lysophosphatidic acid acyltransferase (LPAAT)-β inhibitor CT-32615 triggers caspase-dependent apoptosis, and can overcome resistance to conventional therapeutics (i.e., dexamethasone, doxorubicin, melphalan) in MM cells. In this study, we therefore determined whether CT-32615 could also overcome resistance to PS-341. We first characterized molecular mechanisms of resistance to PS-341 in DHL-4 cells. DHL-4 cells express low levels of caspase-3 and caspase-8; furthermore, no cleavage in caspase-8, caspase-9, caspase-3, poly ADP-ribose polymerase (PARP), or DNA fragmentation factor 45 was triggered by PS-341 treatment. We have previously shown that PS-341 treatment triggers phosphorylation of c-Jun NH2-terminal kinase (JNK), which subsequently induces caspase-dependent apoptosis; conversely, JNK inhibition blocks PS-341-induced apoptosis. We here show that phosphorylation of SEK-1, JNK, and c-Jun are not induced by PS-341 treatment, suggesting that PS-341 does not trigger a stress response in DHL-4 cells. Importantly, CT-32615 inhibits growth of DHL-4 cells in a time- and dose-dependent fashion: a transient G2/M cell cycle arrest induced by CT-32615 is mediated via downregulation of cdc25c and cdc2. CT-32615 triggered swelling and lysis of DHL-4 cells, without caspase/PARP cleavage or TUNEL-positivity, suggesting a necrotic response. Our studies therefore demonstrate that LPAAT-β inhibitor CT-32615 triggers necrosis, even in PS-341-resistant DHL-4 cells, providing the framework for its evaluation to overcome clinical PS-341 resistance and improve patient outcome.

Original languageEnglish (US)
Pages (from-to)3121-3129
Number of pages9
JournalOncogene
Volume24
Issue number19
DOIs
StatePublished - Apr 28 2005

Keywords

  • Bortezomib
  • Caspase
  • Cell cycle
  • Lysophosphatidic acid acyltransferase-β inhibitor
  • Necrosis
  • PS-341

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Hideshima, T., Chauhan, D., Ishitsuka, K., Yasui, H., Raje, N., Kumar, S., Podar, K., Mitsiades, C., Hideshima, H., Bonham, L., Munshi, N. C., Richardson, P. G., Singer, J. W., & Anderson, K. C. (2005). Molecular characterization of PS-341 (bortezomib) resistance: Implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-β inhibitors. Oncogene, 24(19), 3121-3129. https://doi.org/10.1038/sj.onc.1208522