Background:Although the proteasome is a validated anticancer target, the clinical application of its inhibitors has been limited because of inherent systemic toxicity. To broaden clinical utility of proteasome inhibitors as anticancer agents, it is critical to develop strategies to selectively target proteasomes in cancer cells. The immunoproteasome is an alternative form of the constitutive proteasome that is expressed at high levels in cancer tissues, but not in most normal cells in the body.Methods:To validate the immunoproteasome as a chemotherapeutic target, an immunoproteasome catalytic subunit LMP2-targeting inhibitor and siRNA were used. The sensitivity of PC-3 prostate cancer cells to these reagents was investigated using viability assays. Further, a xenograft model of prostate cancer was studied to test the in vivo effects of LMP2 inhibition.Results:A small molecule inhibitor of the immunoproteasome subunit LMP2, UK-101, induced apoptosis of PC-3 cells and resulted in significant inhibition (∼50–60%) of tumour growth in vivo. Interestingly, UK-101 did not block degradation of IκBα in PC-3 cells treated with TNF-α, suggesting that its mode of action may be different from that of general proteasome inhibitors, such as bortezomib, which block IκBα degradation.Conclusion:These results strongly suggest that the immunoproteasome has important roles in cancer cell growth and thus provide a rationale for targeting the immunoproteasome in the treatment of prostate cancer.

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Easy deformation-induced nanostructuring was found in a Ti–Nb–Ta–In β alloy with low stability against α″ martensitic transformation. Upon severe plastic deformation at the sample center, the reversible β→α″ martensitic transformation plays a significant role for grain refinement. A possible mechanism is proposed, in which the formation of fine martensite, the interaction among slip dislocations, martensite and twins, and the reversible transition from α″ back to β phase are considered as the main causes leading to pronounced grain refinement to the nanoscale.

We report ductile bulk metallic glasses based on martensitic alloys. The slowly cooled specimens contain a mixture of parent 'austenite' and martensite phase. The slightly faster cooled bulk metallic glasses with 2-5 nm sized 'austenite'-like crystalline cluster reveal high strength and large ductility (16%). Shear bands propagate in a slither mode in this spatially inhomogeneous glassy structure and undergo considerable 'thickening' from 5-25 nm. A 'stress induced displacive transformation' is proposed to be responsible for both plasticity and work-hardeninglike behavior of these 'M-Glasses'.