Inhibition of p38 MAPK or immunoproteasome overcomes resistance of chronic lymphocytic leukemia cells to Bcl-2 antagonist venetoclax

Autor: Damjan Avsec, Marja Škrlj Miklavčič, Tilen Burnik, Maša Kandušer, Maruša Bizjak, Helena Podgornik, Irena Mlinarič-Raščan
Rok vydání: 2022
Předmět:
Zdroj: Cell death & disease, 13 str. : Ilustr., Vol. 13, art. 860, 2022
COBISS-ID: 24434727
Cell death & disease, vol. 13, no. 860, 2022.
ISSN: 2041-4889
Popis: Chronic lymphocytic leukemia (CLL) is a hematological neoplasm of CD19-positive mature-appearing B lymphocytes. Despite the clinical success of targeted therapies in CLL, the development of resistance diminishes their therapeutic activity. This is also true for the Bcl-2 antagonist venetoclax. We investigated the molecular mechanisms that drive venetoclax resistance in CLL, with a clear focus to provide new strategies to successfully combat it. Activation of CLL cells with IFNγ, PMA/ionomycin, and sCD40L diminished the cytotoxicity of venetoclax. We demonstrated that the metabolic activity of cells treated with 1 nM venetoclax alone was 48% of untreated cells, and was higher for cells co-treated with IFNγ (110%), PMA/ionomycin (78%), and sCD40L (62%). As of molecular mechanism, we showed that PMA/ionomycin and sCD40L triggered translocation of NFκB in primary CLL cells, while IFNγ activated p38 MAPK, suppressed spontaneous and venetoclax-induced apoptosis and induced formation of the immunoproteasome. Inhibition of immunoproteasome with ONX-0914 suppressed activity of immunoproteasome and synergized with venetoclax against primary CLL cells. On the other hand, inhibition of p38 MAPK abolished cytoprotective effects of IFNγ. We demonstrated that venetoclax-resistant (MEC-1 VER) cells overexpressed p38 MAPK and p-Bcl-2 (Ser70), and underexpressed Mcl-1, Bax, and Bak. Inhibition of p38 MAPK or immunoproteasome triggered apoptosis in CLL cells and overcame the resistance to venetoclax of MEC-1 VER cells and venetoclax-insensitive primary CLL cells. In conclusion, the p38 MAPK pathway and immunoproteasome represent novel targets to combat venetoclax resistance in CLL. Nasl. z nasl. zaslona. Opis vira z dne 10. 10. 2022. Št. članka 860. Bibliografija: str. 12-13. ARRS, Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin ARRS, NOBIL - Novi biološki označevalci v levkemiji ARRS, Značilnosti malignih neoplazem, pomembne za diagnozo ter napoved poteka bolezni in izida zdravljenja Ministry of Education, Science, and Sport (MIZŠ) and the European Regional Development Fund, RI-SI-EATRIS
Databáze: OpenAIRE
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