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 1α (HIF-1α) 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-1α 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-1α and FoxO1 expression. Moreover, the promoter region of FoxO1 was directly regulated by HIF-1α. We inhibited HIF-1α 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-1α 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-1α silencing via siRNA.

CONCLUSIONS:

Our data reveal that HIF-1α 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-1α 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.

• Authors: Wei Sun, Bing Wang, Xing-Long Qu, Bi-Qiang Zheng, Wen-Ding Huang, Zheng-Wang Sun, Chun-Meng Wang, Yong Chen
• Journal: Cells (Cells) Vol. 9 Issue 1 (Dec 30 2019) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 31905813 (Publication Type: Journal Article)

Chemical References

• Forkhead Box Protein O1
• HIF1A protein, human
• Heat-Shock Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Reactive Oxygen Species
• SESN3 protein, human
• Catalase
• Superoxide Dismutase
• superoxide dismutase 2

Topics

• Animals
• Apoptosis (drug effects)
• Catalase (metabolism)
• Cell Hypoxia (physiology)
• Cell Line, Tumor
• China
• Forkhead Box Protein O1 (metabolism)
• Heat-Shock Proteins (metabolism)
• Humans
• Hypoxia (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Osteosarcoma (metabolism, pathology)
• Reactive Oxygen Species (metabolism, therapeutic use)
• Signal Transduction
• Superoxide Dismutase (metabolism)
• Xenograft Model Antitumor Assays