Mitochondrial Ca2+ and Apoptosis in Multiple Myeloma

Abstract

Multiple myeloma is a hematological cancer of plasma cells. Proteasome inhibitors, such as Bortezomib (BZ, Velcade/PS‐341) are used to treat myeloma because they induce apoptosis via activation of ER stress. We showed that ER stress results in a transient increase in cytosolic calcium ([Ca2+]c), and subsequent initiation of apoptosis. Since inhibition of mitochondrial Ca2+ ([Ca2+]m) uptake with ruthenium red blocked apoptotic initiation and activation of caspase activity, we analyzed [Ca2+]m in the myeloma line 8226 using Rhod‐2. Although BZ elicits a transient increase in [Ca2+]c, [Ca2+]m was found to rapidy (< 1 min) decrease. Following this initial decrease, two distinct responses were identified; either [Ca2+]m returned to then exceeded baseline, or [Ca2+]m remained below baseline levels. Our results indicate that there are two discrete sub‐populations of myeloma cells with respect to response to BZ which is consistent with the observed efficacy of BZ on <70% of the myeloma population. We propose that the population in which [Ca2+]m remains low is refractory to BZ induced apoptosis. Current studies will test this hypothesis, and aim to further characterize these two sub‐populations of myeloma cells. These data will allow us to identify targets for initiating apoptosis in the BZ refractory population with the goal of increasing the efficacy and specificity of drug treatment.