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

Niyati Vachharajani,Maik Luu,Markus J Hofer,Thorsten Joeris,Georgios Pantazis,Sabrina Hartmann,Sabine Pautz,Immo Prinz,Alexander Visekruna,Elena Jenike,Ulrich Steinhoff

doi:10.18632/oncotarget.14579

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.

Highlights

Individuals suffering from inflammatory bowel disease (IBD) face a high risk of developing colorectal cancer [1]
We reported an up-regulation of proteasome quantity in WT but not in LMP7 deficient mice infected with Listeria monocytogenes [16]
Comparable to this finding, we detected a significant increase in the expression of α4 subunit, which is a structural part of both constitutive and immunproteasomes, on day 8 after induction of colitis by dextran sodium sulfate (DSS) in WT mice

Summary

Introduction

Individuals suffering from inflammatory bowel disease (IBD) face a high risk of developing colorectal cancer [1]. Environmental and genetic factors play a crucial role in the onset of inflammation-driven carcinogenesis whereby the loss of function of tumor suppressors such as adenomatous polyposis coli (APC) and increased activation of β-catenin are mostly accompanied by increased expression of pro-tumorigenic cytokines such as IL-6, TNF-α and IL-17A. Intestinal epithelial cells expressing high levels of TNFR1 are highly sensitive to TNF-α, which is able to induce NFκB-mediated oncogenic pathways [2]. Similar to IL-6 and IL-17A, the new member of the IL-6 cytokine family, IL11, profoundly activates epithelial STAT3 signalling [3]. The hyperactive intestinal immune system provides external factors for intestinal epithelium contributing to its constitutive NF-κB and STAT3 activation, which enhances the cross-talk of intra-tumoral signaling, resulting in excessive proliferation and resistance to apoptosis

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Conclusion