A selective inhibitor of the immunoproteasome subunit LMP2 induces apoptosis in PC-3 cells and suppresses tumour growth in nude mice Article

Wehenkel, M, Ban, JO, Ho, YK et al. (2012). A selective inhibitor of the immunoproteasome subunit LMP2 induces apoptosis in PC-3 cells and suppresses tumour growth in nude mice . British Journal of Cancer, 107(1), 53-62. 10.1038/bjc.2012.243

cited authors

  • Wehenkel, M; Ban, JO; Ho, YK; Carmony, KC; Hong, JT; Kim, KB

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 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. © 2012 Cancer Research UK All rights reserved.

authors

publication date

  • June 26, 2012

published in

Digital Object Identifier (DOI)

start page

  • 53

end page

  • 62

volume

  • 107

issue

  • 1