Targeting the cross-talk between the hedgehog and NF-κB signaling pathways in multiple myeloma

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.