Immunoproteasome in Lung Cancer

Lung cancer is the most common cancer in the world and a highly lethal disease. However, systemic treatments for lung cancer with standard chemotherapy agents are largely ineffective. Thus, novel targets and effective therapy are urgently needed to improve clinical outcomes. The proteasome, the multiprotease complex, regulates many essential signaling pathways by degrading targeted proteins. The FDA approval of bortezomib, the first-in-class proteasome inhibitor, has validated the proteasome as an anticancer target, but its severe systemic toxicity limits broad application. In this regard, the immunoproteasome, an alternative form of the constitutive proteasome, has gained much attention, given that the immunoproteasome is upregulated in cancer cells, but minimally expressed in non-tumor cells. Recently, we have developed an immunoproteasome-specific inhibitor ('UK-101') and found that UK-101 induces apoptotic cell death in prostate cancer. Our long-term goal is to develop a novel lung cancer therapy using the immunoproteasome as a target. In our preliminary studies, we show that LMP2, a major catalytic subunit of the immunoproteasome, is highly expressed in primary lung cancer tissues and non-small cell lung cancer cell lines. In addition, we found that UK-101 induces cell death in lung cancer cells. We also found that cancer cells highly expressing LMP2 are, in general, more sensitive to UK-101 than those expressing a low level of LMP2. However, there was also a case where lung cancer cells expressing LMP2 were resistant to UK-101, suggesting that there may be additional factors influencing cellular sensitivity to UK-101. Interestingly, the human LMP2 has naturally occurring genetic polymorphisms including p.60R>H (allelic frequency of 1 - 34%). However, the functional impact of these LMP2 polymorph isms in lung cancer is not known. In this application, we will 1) determine the expression levels and genetic polymorphisms of LMP2 in clinical lung cancer samples and 2) investigate their influence on the sensitivity of lung cancer cells to the immunoproteasome inhibitor, UK-101. The proposed study will provide important information in evaluating therapeutic potential of the immunoproteasome in lung cancer therapy and identifying factors affecting the tumor response to the immunoproteasome-targeting approach.