Prevention of colitis-associated cancer by selective targeting of immunoproteasome subunit LMP7

Abstract

// Niyati Vachharajani 1 , Thorsten Joeris 2 , Maik Luu 1 , Sabrina Hartmann 1 , Sabine Pautz 1 , Elena Jenike 1 , Georgios Pantazis 3 , Immo Prinz 4 , Markus J. Hofer 3, 5 , Ulrich Steinhoff 1 and Alexander Visekruna 1 1 Institute for Medical Microbiology and Hygiene, Philipps University of Marburg, Marburg, Germany 2 Section of Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, Frederiksberg, Denmark 3 Department of Neuropathology, Philipps University of Marburg, Marburg, Germany 4 Institute of Immunology, Hannover Medical School, Hannover, Germany 5 School of Life and Environmental Sciences, The University of Sydney, New South Wales, Australia Correspondence to: Alexander Visekruna, email: alexander.visekruna@staff.uni-marburg.de Niyati Vachharajani, email: niyati@uni-marburg.de Keywords: colon cancer, inflammation, immunoproteasome, NF-κB Received: September 26, 2016     Accepted: November 30, 2016     Published: January 10, 2017 ABSTRACT Chronic inflammation is a well-known risk factor in development of intestinal tumorigenesis, although the exact mechanisms underlying development of colitis-associated cancer (CAC) still remain obscure. The activity and function of immunoproteasome has been extensively analyzed in the context of inflammation and infectious diseases. Here, we show that the proteasomal immunosubunit LMP7 plays an essential role in development of CAC. Mice devoid of LMP7 were resistant to chronic inflammation and formation of neoplasia, and developed virtually no tumors after AOM/DSS treatment. Our data reveal that LMP7 deficiency resulted in reduced expression of pro-tumorigenic chemokines CXCL1, CXCL2 and CXCL3 as well as adhesion molecule VCAM-1. As a consequence, an impaired recruitment and activity of tumor-infiltrating leukocytes resulting in decreased secretion of cytokines IL-6 and TNF-α was observed. Further, the deletion or pharmacological inhibition of LMP7 and consequent blockade of NF-κB abrogated the production of IL-17A, which possesses a strong carcinogenic activity in the gut. Moreover, in vivo administration of the selective LMP7 inhibitor ONX-0914 led to a marked reduction of tumor numbers in wild-type (WT) mice. Collectively, we identified the immunoproteasome as a crucial mediator of inflammation-driven neoplasia highlighting a novel potential therapeutic approach to limit colonic tumorigenesis.