TAK1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan.

Autor:	Håland E; CEMIR Centre of Molecular Inflammation Research, IKOM, NTNU, Trondheim, Norway.; Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway., Moen IN; CEMIR Centre of Molecular Inflammation Research, IKOM, NTNU, Trondheim, Norway.; Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway.; Department of Hematology, St. Olavs University Hospital, Trondheim, Norway., Veidal E; CEMIR Centre of Molecular Inflammation Research, IKOM, NTNU, Trondheim, Norway.; Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway., Hella H; Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway., Misund K; Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway., Slørdahl TS; Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway.; Department of Hematology, St. Olavs University Hospital, Trondheim, Norway., Starheim KK; CEMIR Centre of Molecular Inflammation Research, IKOM, NTNU, Trondheim, Norway.; Department of Clinical and Molecular Medicine, NTNU, Trondheim, Norway.; Department of Hematology, St. Olavs University Hospital, Trondheim, Norway.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2021 Oct 12; Vol. 12 (21), pp. 2158-2168. Date of Electronic Publication: 2021 Oct 12 (Print Publication: 2021).
DOI:	10.18632/oncotarget.28073
Abstrakt:	Multiple myeloma (MM) is an incurable cancer caused by malignant transformation of plasma cells. Transforming growth factor-β activated kinase 1 (MAP3K7, TAK1) is a major regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. Both NF-κB and MAPK control expression of genes with vital roles for drug resistance in MM. TAK1 is an attractive drug target as it switches these survival pathways to cell death. Our analysis showed that patients with high MAP3K7 expression in the tumor had shorter overall and progression free survival. The TAK1-inhibitors NG25 and 5Z-7-oxozeaenol (5Z-7) were cytotoxic to MM cell lines and patient cells. NG25 reduced expression of MYC and E2F controlled genes, involved in tumor cell growth, cell cycle progression and drug resilience. TAK1 can be activated by genotoxic stress. NG25 and 5Z-7 induced both synergistic and additive cytotoxicity in combination with the alkylating agent melphalan. Melphalan activated TAK1, NF-κB, and the MAPKs p38 and c-Jun N-terminal kinase (JNK), as well as a transcriptional UV-response. This was blocked by NG25, and instead apoptosis was activated. MM induce elevated bone-degradation resulting in myeloma bone disease (MBD), which is the main cause of disability and morbidity in MM patients. NG25 and 5Z-7 reduced differentiation and viability of human bone degrading osteoclasts, suggesting that TAK1-inhibition can have a double beneficial effect for patients. In sum, TAK1 is a promising drug target for MM treatment. Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare. (Copyright: © 2021 Håland et al.)
Databáze:	MEDLINE
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