Inhibition and deficiency of the immunoproteasome subunit LMP7 suppress the development and progression of colorectal carcinoma in mice
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Julia Koerner1,2, Thomas Brunner2,3 and Marcus Groettrup1,2,4
1Division of Immunology, Department of Biology, University of Konstanz, Konstanz, Germany
2Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Konstanz, Germany
3Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
4Biotechnology Institute Thurgau at the University of Konstanz (BITg), Kreuzlingen, Switzerland
Marcus Groettrup, email: [email protected]
Keywords: colorectal cancer, immunoproteasome, LMP7, AOM/DSS, ApcMin/+
Received: December 02, 2016 Accepted: January 11, 2017 Published: February 07, 2017
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.
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