a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China.
b School of Medicine and Life Sciences , Nanjing University of Chinese Medicine , Nanjing , 210023 , P.R. China.
Leuk Lymphoma. 2019 Mar;60(3):772-781. doi: 10.1080/10428194.2018.1493727. Epub 2019 Jan 15.
Multiple myeloma (MM) is an incurable plasma cell malignancy. Aberrant activation of the Hedgehog (Hh) and NF-κB signaling pathways is observed in MM and plays a pivotal role in the development of MM by promoting myeloma cell growth, survival, and drug resistance. In this study, we found that the Sonic Hh (SHh) ligand in the bone marrow microenvironment is responsible for the enhancement of NF-κB activity in MM cell lines NCI-H929 and U266. Notably, we discovered that Hh signaling regulates NF-κB through its classical pathway (SHh/PTCH1/SMO/GLI1) in MM cells. Meanwhile, non-classical pathway by SMO recruitment of TRAF6 to ubiquitination is also involved in it. Moreover, the SMO inhibitor cyclopamine enhances the cytotoxic effects of bortezomib in MM cell lines. Our study reveals the cross-talk between Hh members and the NF-κB pathway in the myeloma cells and provides a theoretical basis for combined utilization of Hh members and proteasome inhibition in MM.
多发性骨髓瘤（MM）是一种不可治愈的浆细胞恶性肿瘤。Hedgehog（Hh）和 NF-κB 信号通路的异常激活在 MM 中观察到，并通过促进骨髓瘤细胞生长、存活和耐药性在 MM 的发展中发挥关键作用。在这项研究中，我们发现骨髓微环境中的 Sonic Hh（SHh）配体负责增强 MM 细胞系 NCI-H929 和 U266 中的 NF-κB 活性。值得注意的是，我们发现 Hh 信号通过其经典途径（SHh/PTCH1/SMO/GLI1）在 MM 细胞中调节 NF-κB。同时，SMO 募集 TRAF6 进行泛素化也参与其中。此外，SMO 抑制剂环巴胺增强了硼替佐米在 MM 细胞系中的细胞毒性作用。我们的研究揭示了骨髓瘤细胞中 Hh 成员与 NF-κB 通路之间的串扰，并为联合利用 Hh 成员和蛋白酶体抑制在 MM 中的应用提供了理论依据。
