Das Immunoproteasom als potentielles therapeutisches Zielmolekül bei der Entstehung des Colitis-assoziierten Karzinom
Zusammenfassung der Projektergebnisse
During the founding period, as applied, we focused on the impact of immunoproteasome on the colonic inflammation and colitis-associated cancer. Moreover, the characterization of a novel L. acidophilus-derived proteasome inhibitor was performed in the second part of the project. The enzymatic activity of the immunoproteasome is implicated in a number of pathological disorders, including various inflammatory and autoimmune diseases and hematological malignancies. We were able to show that the TKO mice devoid of functional immunoproteasomes display reduced number of colonic tumors in the experimental model of AOM/DSS-induced carcinogenesis. Furthermore, TKO mice displayed marked defects in cytokines with pro-inflammatory properties such as IL-17A, IL-6, IL-1β and TNF-α, which are important players in the development of inflammatory diseases. We were capable of demonstrating that an elevated production of pro-tumorigenic cytokines TNF-α, IL-6 and IL-17A, as well as recruitment of pro-inflammatory leukocytes to the colon, are mechanistically connected to the increased enzymatic activity of immunoproteasomes. Collectively, the inhibition of the immunoproteasome and its chymotrypsin-like activity in immune cells might be an innovative strategy in the therapy of ulcerative colitisassociated cancer.
Projektbezogene Publikationen (Auswahl)
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Pro- and Antitumorigenic Capacity of Immunoproteasomes in Shaping the Tumor Microenvironment. Cancer Immunology Research, 9(6), 682-692.
Leister, Hanna; Luu, Maik; Staudenraus, Daniel; Lopez Krol, Aleksandra; Mollenkopf, Hans-Joachim; Sharma, Arjun; Schmerer, Nils; Schulte, Leon N.; Bertrams, Wilhelm; Schmeck, Bernd; Bosmann, Markus; Steinhoff, Ulrich & Visekruna, Alexander
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The Role of Immunoproteasomes in Tumor-Immune Cell Interactions in Melanoma and Colon Cancer. Archivum Immunologiae et Therapiae Experimentalis, 70(1).
Leister, Hanna; Krause, Felix F.; Mahdavi, Rouzbeh; Steinhoff, Ulrich & Visekruna, Alexander
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Immunoproteasome deficiency results in age-dependent development of epilepsy. Brain Communications, 6(1).
Leister, Hanna; Krause, Felix F.; Gil, Beatriz; Prus, Ruslan; Prus, Inna; Hellhund-Zingel, Anne; Mitra, Meghma; Da Rosa Gerbatin, Rogerio; Delanty, Norman; Beausang, Alan; Brett, Francesca M.; Farrell, Michael A.; Cryan, Jane; O.’Brien, Donncha F.; Henshall, David C.; Helmprobst, Frederik; Pagenstecher, Axel; Steinhoff, Ulrich; Visekruna, Alexander & Engel, Tobias
