ABSTRACT
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.
Subject(s)
Cysteine Endopeptidases/genetics , Prostatic Neoplasms/genetics , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cysteine Endopeptidases/drug effects , Dipeptides/pharmacology , Humans , Male , Mice , Mice, Nude , Neoplasm Transplantation , Organosilicon Compounds/pharmacology , RNA, Small Interfering/pharmacology , Transplantation, HeterologousABSTRACT
We present in this paper a quantitative study of an effect, in which a low-energy free electron is captured and violently accelerated to GeV final kinetic energy by a stationary extra-high-intensity laser beam (Q0 identical witheE/m(e)omegac greater, similar100). The conditions under which this phenomenon can occur, such as the momentum range, incident angle of the incoming electron, the waist width of the laser beam, etc., have been investigated in detail.
