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 IBα 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 IBα 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.
|Number of pages||10|
|Journal||British Journal of Cancer|
|State||Published - Jun 26 2012|
Bibliographical noteFunding Information:
This work has been supported by Graduate School Academic Year, Kentucky Opportunity, Presidential, and American Foundation for Pharmaceutical Education Fellowships (MW). KBK gratefully acknowledges the support of the Markey Cancer Foundation, NIH (CA131059), and DoD (W81XWH-08-1-0092). JTH is grateful for the Korea Research Foundation (MRC, R13-2008-001-00000-00) for financial support. We thank members of the Hong and Kim laboratories for their helpful comments on the manuscript. We are grateful to Dr Wooin Lee for helping with the collection of IHC and fluorescent images.
- antitumour activity
- target validation
ASJC Scopus subject areas
- Cancer Research