Abstract
Multiple myeloma is an incurable plasma cell malignancy. The 26S proteasome inhibitor, bortezomib, selectively induces apoptosis in multiple myeloma cells; however, the mechanism by which this compound acts remains unknown. Here, we, using immunoblotting analysis, observed that the expression of BiP, CHOP, and XBP-1 is up-regulated in bortezomib-induced apoptosis in human multiple myeloma cell lines NCI-H929 and RPMI-8226/S, strongly suggesting that endoplasmic reticulum (ER) stress response or the unfolded protein response (UPR), a signaling pathway activated by the accumulation of unfolded proteins within ER, is initiated. In the meantime, we also showed that bortezomib inhibited classic ER stressor brefeldin A-induced up-regulation of prosurvival UPR components BiP and XBP-1, resulting in increased induction of apoptosis in multiple myeloma cell lines, raising the possibility that bortezomib induces apoptosis of multiple myeloma cells by means of evoking the severe ER stress but disrupting the prosurvival UPR required. Using caspase inhibitors and a RNA interference approach, we finally confirmed that bortezomib-triggered apoptosis in multiple myeloma cells is dependent on caspase-2 activation, which is associated with ER stress and required for release of cytochrome c, breakdown of mitochondrial transmembrane potential, and its downstream caspase-9 activation. Taken together, these data strongly suggest that caspase-2 can serve as a proximal caspase that functions upstream of mitochondrial signaling during ER stress-induced apoptosis by bortezomib in multiple myeloma cells.
Highlights
Bortezomib (Velcade, formerly PS-341), a specific and selective inhibitor of 26S proteasome [1], has shown remarkable therapeutic efficacy in multiple myeloma, a plasma cell malignancy (2 – 6)
It has been shown that multiple myeloma cells are more sensitive than other cell types to proteasome inhibition because of their large volume of immunoglobulin production [18], which appears to lower their threshold for induction of proapoptotic unfolded protein response (UPR) following any additional stress to the endoplasmic reticulum (ER)
To elucidate the apoptotic mechanisms used by bortezomib, we studied the effects of this drug on ER stressinduced caspase activation and mitochondrial permeability in the initiation of cell death in human multiple myeloma cell lines
Summary
Bortezomib (Velcade, formerly PS-341), a specific and selective inhibitor of 26S proteasome [1], has shown remarkable therapeutic efficacy in multiple myeloma, a plasma cell malignancy (2 – 6). Multiple myeloma cells produce and secrete abundant immunoglobulin This requires a highly developed endoplasmic reticulum (ER) and production of chaperone proteins that effect proper translation and folding [11]. A signaling pathway called the unfolded protein response (UPR), or ER stress response, ensures that the plasma cells can handle the proper folding of proteins and prevent the aggregation of the accumulating misfolded proteins [12]. These misfolded proteins are recognized by ER qualitycontrol systems and targeted for ER-associated protein degradation, which involves the retrograde translocation of the misfolded proteins out of the ER and subsequent degradation by cytosolic 26S proteasomes (13 – 15). It has been shown that multiple myeloma cells are more sensitive than other cell types to proteasome inhibition because of their large volume of immunoglobulin production [18], which appears to lower their threshold for induction of proapoptotic UPR following any additional stress to the ER
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