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.
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Abbreviations
- MM:
-
multiple myeloma
- LPA:
-
lysophosphatidic acid
- LPAAT:
-
LPA acyltransferase
- PARP:
-
poly (ADP)-ribose polymerase
- Dex:
-
dexamethasone
- Dox:
-
doxorubicin
- BM:
-
bone marrow
- BMSC:
-
BM stromal cell
- MTT:
-
3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyl tetrazolium bromide
- PI:
-
propidium iodine
- Hsp:
-
heat–shock protein
- JNK:
-
c-Jun NH2-terminal kinase
- DFF:
-
DNA fragmentation factor
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Acknowledgements
This study is supported by National Institutes of Health SPORE IP50 CA10070-01, PO-1 78378, and RO-1 CA 50947 Grants; the Doris Duke Distinguished Clinical Research Scientist Award (KCA); the Multiple Myeloma Research Foundation (TH); and the Cure for Myeloma Research Fund (KCA).
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Hideshima, T., Chauhan, D., Ishitsuka, K. et al. Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-β inhibitors. Oncogene 24, 3121–3129 (2005). https://doi.org/10.1038/sj.onc.1208522
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DOI: https://doi.org/10.1038/sj.onc.1208522
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