Abstract
The inhibitor-of-apoptosis family member survivin has been reported to inhibit apoptosis and regulate mitosis and cytokinesis. In multiple myeloma, survivin has been described to be involved in downstream sequelae of various therapeutic agents. We assessed 1093 samples from previously untreated patients, including two independent cohorts of 392 and 701 patients, respectively. Survivin expression was associated with cell proliferation, adverse prognostic markers, and inferior event-free and overall survival, supporting the evaluation of survivin as a therapeutic target in myeloma. The small molecule suppressant of survivin--YM155--is in clinical development for the treatment of solid tumors. YM155 potently inhibited proliferation and induced apoptosis in primary myeloma cells and cell lines. Gene expression and protein profiling revealed the critical roles of IL6/STAT3-signaling and the unfolded protein response in the efficacy of YM155. Both pathways converged to down regulate anti-apoptotic Mcl-1 in myeloma cells. Conversely, growth inhibition and apoptotic cell death by YM155 was rescued by ectopic expression of Mcl-1 but not survivin, identifying Mcl-1 as the pivotal downstream target of YM155 in multiple myeloma. Mcl-1 expression was likewise associated with adverse prognostic markers, and inferior survival. Our results strongly support the clinical evaluation of YM155 in patients with multiple myeloma.
Highlights
Multiple myeloma (MM) is a malignant disease that is characterized by clonal expansion of terminally differentiated B cells
In agreement with microarray and qRTPCR-data, survivin protein could be detected in 12/12 MM cell lines, being absent in 2/2 bone marrow stromal cell samples used as control (Figure 1B)
As IL-6 stimulation sensitized OPM-2 cells to treatment with YM155, we examined the phosphorylation of STAT3 and the protein expression of survivin and Mcl-1 in IL-6 stimulated cells exposed to YM155
Summary
Multiple myeloma (MM) is a malignant disease that is characterized by clonal expansion of terminally differentiated B cells. Important for MM cell survival and therapeutic resistance are impaired mechanisms of apoptosis. The anti-apoptotic Bcl-2 family member Mcl-1, in particular, seems to be essential for MM cell survival [4,5,6,7]. Survivin is a member of the IAP (inhibitors of apoptosis) protein family, encoded by the BIRC5 gene, and is highly expressed in cancer cells while virtually absent in most differentiated normal tissues [8, 9]. Survivin has been shown to counteract apoptosis induction upstream of effector caspases [15] and to have an essential role in cell proliferation by regulating spindle assembly and microtubule attachment to the kinetochore as a member of the chromosomal passenger complex [16, 17]. Long-term knockdown of survivin resulted in moderate inhibition of MM cell growth and increased drug sensitivity [21]
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