The immunoproteasome inhibition as a novel therapeutic strategy for the treatment of colitis-associated cancer

• Applicant: Professor Dr. Alexander Visekruna
• Subject Area: Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457407471

In patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), the risk of developing colorectal cancer (CRC) increases with progression of severity and duration of the disease. The ubiquitin-proteasme proteolytic machinery is important in regulating immune response. In IBD, the aberrant activation of the immunoproteasome is associated with enhanced secretion of proinflammatory cytokines. While the constitutively proteasome is expressed ubiquitously in all cell types, the high immunoproteasome levels are predominately found in the activated immune cells in IBD patients. The immunoptoreasome activity appears to be crucial factor supporting chronic inflammation which predisposes colonic epithelial cells to tumor development. At the present, non-specific proteasome inhibitors such as Carfilzomib and Bortezomib have been shown to exhibit a strong therapeutic capacity in hematologic malignancies. In this project, we will investigate whether the novel, uncharacterized Lactobacillus acidophilus-derived immunoproteasome inhibitor has protective effects on inflammation-driven carcinogenesis in the colon. Moreover, mice deficient for immunoproteasome will be investigated in the AOM/DSS model of colitis-associated cancer.

• DFG Programme: Research Grants