ArticleHaematologica2021
TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma.
Article in Haematologica, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 30 citations in OpenAlex.
- Tumor-derived CTHRC1 mediates ITGB3-dependent osteoclast differentiation to promote prostate cancer bone metastasis.Oncogene · 2026Article
- Mutual amplification of sensory nerve outgrowth and tumor progression in myeloma.Haematologica · 2026Article
- Dual regulation of phaseol on osteoclast formation and osteoblast differentiation by targeting TAK1 kinase for osteoporosis treatment.Journal of advanced research · 2025Article
- TAK1 Promotes an Immunosuppressive Tumor Microenvironment through Cancer-Associated Fibroblast Phenotypic Conversion in Pancreatic Ductal Adenocarcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- A novel 2-iminobenzimidazole compound, XYA1353, displays in vitro and in vivo anti-myeloma activity via targeting NF-κB signaling.Molecular and cellular biochemistry · 2024Article
- Discovery of imidazo[1,2-RSC medicinal chemistry · 2024Article
- Therapeutic efficacy of the resorcylic acid lactone LL-Z1640-2 for adult T-cell leukaemia/lymphoma.EJHaem · 2023Article
- Mechanisms of preferential bone formation in myeloma bone lesions by proteasome inhibitors.International journal of hematology · 2023Article
- An overview of pim kinase as a target in multiple myeloma.Cancer medicine · 2023Review
- Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents.Journal of bone and mineral metabolism · 2023Review
- Role of NF-κB Signaling in the Interplay between Multiple Myeloma and Mesenchymal Stromal Cells.International journal of molecular sciences · 2023Review
- TAK1-inhibitors did not reduce disease burden in a Vκ*MYC model of multiple myeloma.BMC research notes · 2022Article
- Targeting CAM-DR and Mitochondrial Transfer for the Treatment of Multiple Myeloma.Current oncology (Toronto, Ont.) · 2022Review
- Mechanical unloading aggravates bone destruction and tumor expansion in myeloma.Haematologica · 2022Article
- TGF-β-activated kinase-1 inhibitor LL-Z1640-2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF-α and RANKL expression.Clinical & translational immunology · 2022Article
- Pathogenesis and treatment of multiple myeloma bone disease.The Japanese dental science review · 2021Review
- TAK1-inhibitors are cytotoxic for multiple myeloma cells alone and in combination with melphalan.Oncotarget · 2021Article
- Review
- Beraprost ameliorates postmenopausal osteoporosis by regulating Nedd4-induced Runx2 ubiquitination.Cell death & disease · 2021Article
- Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-β-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.
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