Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, the pathogenesis of which remain largely unknown. Small ubiquitin-like modifier (SUMO)-Specific Protease 2 (SENP2) has been reported to serve as a tumor suppressor in hepatocellular carcinoma cells. The aim of the present study was to investigate the critical role of SENP2 in OS cells. Using reverse transcription-quantitative polymerase chain reaction and western blot assays, it was observed that SENP2 was significantly downregulated in clinical OS tissues compared with adjacent normal samples. Ectopic expression of SENP2 resulted in the suppression of proliferation, migration and invasion in OS cells, whereas SENP2 knockdown by CRISPR-Cas9-based gene editing had the opposite effect. SENP2 is associated with the proteasome-dependent ubiquitination and degradation of SRY-box-9 (SOX9). SOX9 silencing impaired SENP2-depletion-induced accelerated cell growth and migration. Together, these results suggest that SOX9 is a critical downstream effector of the tumor suppressor SENP2 in OS.
Background Osteosarcoma is the most frequent malignant bone malignancy and the current treatments are ineffective. Ivermectin, an anti-protozoal drug, has been shown to have anti-cancer activity. This work investigated the potential of repurposing ivermectin to augment chemotherapy’s efficacy in osteosarcoma. Methods Proliferation, migration and apoptosis assays were performed in ivermectin-treated osteosarcoma cells. Combination studies were performed. Osteosarcoma xenograft mouse model was established to investigate the in vivo efficacy of ivermectin. Intracellular reactive oxygen species (ROS) and mitochondrial superoxide, membrane potential, ATP, 8-OHdG level, protein carbonylation and lipid peroxidation were determined after ivermectin treatment. Results Ivermectin was effective and acted synergistically with doxorubicin in osteosarcoma cells regardless of cellular origin and genetic profiling. This was achieved through suppressing inhibiting growth and migration, and inducing caspase-dependent apoptosis. Ivermectin also significantly inhibited osteosarcoma growth in vivo and its combination with doxorubicin resulted in much greater efficacy than doxorubicin alone. Importantly, the effective dose of ivermectin was clinically feasible and did not cause significant toxicity in mice. Mechanistical analysis showed that ivermectin induced oxidative stress and damage, and mitochondrial dysfunction. Conclusions Our findings indicate that ivermectin has utility in treating patients with osteosarcoma, especially those resistant to chemotherapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.