Soft coral-derived Aspernolide A suppressed non-small cell lung cancer induced osteolytic bone invasion via the c-Fos/NFATC1 signaling pathway

Background: The incidence of distant metastases is over 30% in advanced non-small cell lung cancer (NSCLC) patients. In particular, bone is reported as the most common site of distant metastasis NSCLC. Bone metastases (BM) have a consequence of serious skeletal-related events (SREs) leading to the reduced overall survival (OS) and quality of life of NSCLC patients. Inhibition of osteolytic lesions and regulation crosstalk between metastatic NSCLC cells and bone microenvironment are the key to treating NSCLC. Due to the lack of effective treatments against NSCLC with bone metastasis, screening and identification of novel agents against both NSCLC and osteoclast effects are critically needed. Methods: We assessed the effects of Aspernolide A (AA) on osteolysis and RANKL-induced pathways activation, bone resorption and F-actin ring formation in vitro. We evaluated AA effects on NCI-H460 and A549 cells in vitro through wound healing assay and transwell assay. Furthermore, we assessed the effects of AA in vivo using an intratibial xenograft NSCLC nude mouse model, followed by micro-computed tomography(micro-CT) and TRAcP staining. Results: In our study, AA, a soft coral-derived agent, was shown to inhibit osteoclastogenesis via suppression of nuclear factor (NF)-Kappa Bp65, ERK, AKT and P38 phosphorylation, and then suppress the RANKL-induced c-Fos and NFATc1 activities in bone marrow macrophages (BMMs). Furthermore, AA reduced the migration and invasion of NSCLC cells through diminishing the expression of MMP9, MMP7, and N-cadherin proteins and upregulating E-cadherin expression in vitro, as well as inhibited the phosphorylation of ERK, AKT, P38, and NF-Kappa Bp65. It was also demonstrated that administration of AA could help prevent NSCLC-induced bone destruction by attenuating NSCLC development and osteoclast activity in vivo. Conclusions: Collectively, these findings indicated that Aspernolide A is a potential candidate for NSCLC-induced osteolytic bone destruction.