TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma.
TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma.
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DOI：
10.3324/haematol.2019.234476
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发表时间：
2021-05-01
期刊：
影响因子：
10.1
通讯作者：
Abe M
中科院分区：
文献类型：
--
作者：
Teramachi J;Tenshin H;Hiasa M;Oda A;Bat-Erdene A;Harada T;Nakamura S;Ashtar M;Shimizu S;Iwasa M;Sogabe K;Oura M;Fujii S;Kagawa K;Miki H;Endo I;Haneji T;Matsumoto T;Abe M
沿着肿瘤进展，多发性骨髓瘤（MM）的骨髓微环境发生了改变，这是MM独特病理生理学的基础，并赋予MM细胞侵袭性和耐药性。TGF-b激活的激酶1（TAK 1）介导广泛的细胞内信号传导途径。我们在此证明，TAK 1在MM细胞中组成性过表达和磷酸化，TAK 1抑制可抑制NF-κB、p38 MAPK、ERK和STAT 3的活化，从而降低MM生长和存活的关键介质（包括PIM 2、MYC、Mcl- 1、IRF 4和Sp1）的表达，同时沿着MM细胞中血管生成因子VEGF的显著降低。有趣的是，在与MM细胞共培养的骨髓基质细胞（BMSC）中，TAK 1磷酸化也被诱导沿着血管细胞粘附分子-1（VCAM-1）的上调，这促进了MM细胞-BMSC粘附，同时诱导BMSC产生IL-6和核因子κ-B配体（RANKL）受体激活因子。TAK 1抑制有效地损害MM细胞与BMSC的粘附，从而破坏BMSC对MM细胞生长和存活的支持。此外，TAK 1抑制抑制骨髓细胞与MM细胞共培养物中RANKL增强的破骨细胞生成，并恢复MM细胞或MM中过度产生的成骨细胞生成抑制因子抑制的成骨细胞分化。最后，用TAK 1抑制剂LLZ 1640 -2治疗显著抑制MM肿瘤生长，并防止小鼠MM模型中的骨破坏和丢失。因此，TAK 1抑制可能是一种有前途的治疗选择，不仅靶向MM细胞，而且靶向MM中偏斜的骨髓微环境。
Along with 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-b-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 in order 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 (BMSC) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-B ligand (RANKL) expression by BMSC. TAK1 inhibition effectively impaired MM cell adhesion to BMSC to disrupt the support of MM cell growth and survival by BMSC. 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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影响因子：
20.3
作者：
Lu, Jing;Zavorotinskaya, Tatiana;Garcia, Pablo D.
通讯作者：
Garcia, Pablo D.
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作者：
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20.3
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