Abstract
Resistance to the proteasome inhibitor bortezomib is an emerging clinical problem whose mechanisms have not been fully elucidated. We considered the possibility that this could be associated with enhanced proteasome activity in part through the action of the proteasome maturation protein (POMP). Bortezomib-resistant myeloma models were used to examine the correlation between POMP expression and bortezomib sensitivity. POMP expression was then modulated using genetic and pharmacologic approaches to determine the effects on proteasome inhibitor sensitivity in cell lines and in vivo models. Resistant cell lines were found to overexpress POMP, and while its suppression in cell lines enhanced bortezomib sensitivity, POMP overexpression in drug-naive cells conferred resistance. Overexpression of POMP was associated with increased levels of nuclear factor (erythroid-derived 2)-like (NRF2), and NRF2 was found to bind to and activate the POMP promoter. Knockdown of NRF2 in bortezomib-resistant cells reduced POMP levels and proteasome activity, whereas its overexpression in drug-naive cells increased POMP and proteasome activity. The NRF2 inhibitor all-trans-retinoic acid reduced cellular NRF2 levels and increased the anti-proliferative and pro-apoptotic activities of bortezomib in resistant cells, while decreasing proteasome capacity. Finally, the combination of all-trans-retinoic acid with bortezomib showed enhanced activity against primary patient samples and in a murine model of bortezomib-resistant myeloma. Taken together, these studies validate a role for the NRF2/POMP axis in bortezomib resistance and identify NRF2 and POMP as potentially attractive targets for chemosensitization to this proteasome inhibitor.
Highlights
Acquired proteasome inhibitor resistance emerges in myeloma patients through incompletely understood mechanisms
Bortezomib-resistant Cells Overexpress proteasome maturation protein (POMP)—Previous studies from our group determined that bortezomib-resistant myeloma cells exposed to proteasome inhibitors showed a more rapid recovery of the chymotrypsin-like proteasome activity [27]
We considered the possibility that this could be due to more rapid assembly of new proteasomes and increased proteasome capacity, and analysis of gene expression profiling data comparing bortezomib-resistant cells with their sensitive counterparts revealed up-regulation of POMP
Summary
Acquired proteasome inhibitor resistance emerges in myeloma patients through incompletely understood mechanisms. The combination of all-trans-retinoic acid with bortezomib showed enhanced activity against primary patient samples and in a murine model of bortezomib-resistant myeloma Taken together, these studies validate a role for the NRF2/POMP axis in bortezomib resistance and identify NRF2 and POMP as potentially attractive targets for chemosensitization to this proteasome inhibitor. A more recent study demonstrated that proteasome inhibitor resistance occurred through emergence of plasmablasts with reduced immunoglobulin production [25] These precursor cells have a decreased proteasome load and better balance between load and capacity, thereby reducing cellular stress and apoptotic sensitivity. If this were the only mechanism of acquired resistance, all refractory patients would have oligo-secretory or non-secretory myeloma, which is not the case [15,16,17]. Suppression of either NRF2 or POMP using either short hairpin (sh) RNAs or a pharmacologic agent restored sensitivity in cell lines, primary plasma cells, and an in vivo myeloma model
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