Mitochondrial superoxide dismutase 2 mediates γ-irradiation-induced cancer cell invasion

Abstract

Sublethal doses of γ-rays promote cancer cell invasion by stimulating a signaling pathway that sequentially involves p53, sulfatase 2 (SULF2), β-catenin, interleukin-6 (IL-6), signal transducer and activator of transcription 3 (STAT3), and Bcl-XL. Given that Bcl-XL can increase O2•− production by stimulating respiratory complex I, the possible role of mitochondrial reactive oxygen species (ROS) in γ-irradiation-induced cell invasion was investigated. Indeed, γ-irradiation promoted cell invasion by increasing mitochondrial ROS levels, which was prevented by metformin, an inhibitor of complex I. γ-Irradiation-stimulated STAT3 increased the expression of superoxide dismutase 2 (SOD2), a mitochondrial enzyme that catalyzes the conversion of O2•− to hydrogen peroxide (H2O2). In contrast to O2•−, H2O2 functions as a signaling molecule. γ-Irradiation consistently stimulated the Src-dependent invasion pathway in a manner dependent on both complex I and SOD2. SOD2 was also essential for the invasion of un-irradiated cancer cells induced by upregulation of Bcl-XL, an intracellular oncogene, or extracellular factors, such as SULF2 and IL-6. Overall, these data suggested that SOD2 is critical for the malignant effects of radiotherapy and tumor progression through diverse endogenous factors.Cancer treatment: Stopping the spread after radiotherapyA drug usually used to treat type 2 diabetes may also help to prevent cancer relapse following radiotherapy, which is commonly used to kill cancer cells. However, any tumor cells that survive radiation are highly invasive, sometimes causing tumors to spread. Hong-Duck Um and co-workers at the Korea Institute of Radiological & Medical Sciences in Seoul, South Korea, noticed that the surviving cells often showed higher levels of a key enzyme, superoxide dismutase 2 (SOD2), which is involved in energy production in the cellular powerhouse, the mitochondria. Artificially increasing levels of SOD2, without radiation, made cells more invasive. Treatment with metformin, which prevents production of the molecule that SOD2 acts on, prevented cells from becoming invasive. SOD2 has been implicated in many cancers, and is therefore a very promising therapeutic target.