Abstract
New treatment options and drug targets for colorectal carcinoma are a pressing medical need. Inflammation and pro-inflammatory cytokines produced by Th1 and Th17 cells like IL-6, TNF, IL-17 and IL-23 promote the development and growth of colorectal cancer (CRC). The immunoproteasome is a proteasome subtype highly expressed in immune cells but also in the intestine. Since the immunoproteasome promotes Th1 and Th17 differentiation and pro-inflammatory cytokine production, we investigated here whether deficiency or inhibition of the immunoproteasome subunit LMP7 would interfere with CRC development and exacerbation in preventive and therapeutic mouse models. Treatment with the LMP7 inhibitor ONX 0914 blocked tumor initiation and progression in either chemically-induced (AOM/DSS) or transgenic mouse models (ApcMin/+) of colon carcinogenesis. ONX 0914 treatment strongly reduced tumor numbers and CRC-associated loss of body weight while the survival rates were significantly enhanced. Moreover, genetic LMP7 deficiency markedly reduced the tumor burden in AOM/DSS induced wild type and ApcMin/+ mice. In conclusion, we show that the immunoproteasome is involved in CRC development and progression and we identify LMP7 as a new potential drug target for the treatment of CRC.
Highlights
Colorectal cancer (CRC) is the third most frequently diagnosed and lethal cancer type worldwide [1]
Since the immunoproteasome promotes Th1 and Th17 differentiation and pro-inflammatory cytokine production, we investigated here whether deficiency or inhibition of the immunoproteasome subunit LMP7 would interfere with colorectal cancer (CRC) development and exacerbation in preventive and therapeutic mouse models
Treatment with the LMP7 inhibitor ONX 0914 suppresses the formation of inflammationmediated colon carcinogenesis in the AOM/dextran sodium sulfate (DSS) model
Summary
Colorectal cancer (CRC) is the third most frequently diagnosed and lethal cancer type worldwide [1]. CRC develops from adenomatous precursor lesions by a complex interaction of environmental carcinogens, the accumulation of independent genetic aberrations in oncogenes or tumor suppressor genes, and the host immune system [2]. Long-term inflammatory conditions of the gastrointestinal mucosa as a hallmark of patients suffering from inflammatory bowel disease (IBD), including Ulcerative Colitis (UC) and Crohn’s Disease (CD), pose a significant risk factor for the development of colon cancer as shown both in clinical studies as well as mouse models of chronic inflammation [3]. The clinical outcome and prognosis of CRC is strongly influenced by the type of immune response generated, especially with respect to T helper cell differentiation
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