Metabolism of Reactive Oxygen Species in Osteosarcoma and Potential Treatment Applications.

ABSTRACT: BACKGROUND:The present study was designed to explore the underlying role of hypoxia-inducible factor 1? (HIF-1?) in reactive oxygen species (ROS) formation and apoptosis in osteosarcoma (OS) cells induced by hypoxia. METHODS:In OS cells, ROS accumulated and apoptosis increased within 24 h after exposure to low HIF-1? expression levels. A co-expression analysis showed that HIF was positively correlated with Forkhead box class O1 (FoxO1) expression and negatively correlated with CYP-related genes from the National Center for Biotechnology Information's Gene Expression Omnibus (NCBI GEO) datasets. Hypoxia also considerably increased HIF-1? and FoxO1 expression. Moreover, the promoter region of FoxO1 was directly regulated by HIF-1?. We inhibited HIF-1? via siRNA and found that the ROS accumulation and apoptosis induced by hypoxia in OS cells decreased. In this study, a murine xenograft model of BALB-c nude mice was adopted to test tumour growth and measure the efficacy of 2-ME + As2O3 treatment. RESULTS:Ad interim knockdown of HIF-1? also inhibited manganese-dependent superoxide dismutase (MnSOD), catalase and sestrin 3 (Sesn3) expression in OS cells. Furthermore, hypoxia-induced ROS formation and apoptosis in OS cells were associated with CYP450 protein interference and were ablated by HIF-1? silencing via siRNA. CONCLUSIONS:Our data reveal that HIF-1? inhibits ROS accumulation by directly regulating FoxO1 in OS cells, which induces MnSOD, catalase and Sesn3 interference, thus resulting in anti-oxidation effects. The combination of an HIF-1? inhibitor (2-mercaptoethanol,2-ME) and ROS inducer (arsenous oxide, As2O3) can prohibit proliferation and migration and promote apoptosis in MG63 cells in vitro while inhibiting tumour growth in vivo.

SUBMITTER: Sun W 

PROVIDER: S-EPMC7017125 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature