Inhibition and deficiency of the immunoproteasome subunit LMP7 suppress the development and progression of colorectal carcinoma in mice

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.

Amelioration of autoimmunity with an inhibitor selectively targeting all active centres of the immunoproteasome

“…Whether the epoxyketone‐peptide proteasome inhibitors, LU‐001i or LU‐005i, are affected by MDR1 remains to be determined. It has been found that inhibiting the immunoproteasome prevents the development of autoimmune diseases and of colitis‐associated cancer (Koerner et al, ; Vachharajani et al, ) in several preclinical animal models (summarized in Basler et al, ). To elucidate the potency of LU‐005i in vivo in an inflammatory disease, we chose to use the DSS‐induced colitis model as a proof of principle.…”

Co‐inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity

“…Hence, ONX 0914 was used as the prototype LMP7-selective inhibitor in many studies. LMP7 inhibition with ONX 0914, for example, protected from immunopathological damage in the brain after virus infection [4], exacerbated the pathogenesis of experimental systemic Candida albicans infection [5], protected from colitis-associated cancer formation [6,7], and prevented several autoimmune diseases in pre-clinical mouse models [3,[8][9][10][11][12][13][14] (summarized in Ref. [13]).…”

The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis

“…activation. SAA increased IL-6 secretion in a TLR2-dependent manner in dermal fibroblasts 61 , suggesting that the SAA/TLR2 signaling axis may be a contributor to the inflammatory In addition, immunoproteasomes are known to regulate the production of pro-inflammatory cytokines such as IL-6, IFN-γ, TNF-α, GM-CSF, and IL-23 thereby affecting innate immune signaling 33,80 . Several of these cytokines are known to be involved in the pathogenesis of scleroderma and therapeutic strategies aiming at blocking of these pathways have been tested although with differing outcomes 36 .…”