Arginase-II promotes melanoma and lung cancer cell growth by regulating Sirt3-mtROS axis.

BACKGROUND: Aberrant mitochondrial metabolism is a key source of massive mitochondrial reactive oxygen species (mtROS) in tumour cells. Arginase-II (Arg-II), a widely expressed mitochondrial metabolic enzyme, has recently been shown to enhance mtROS production and melanoma progression. However, how Arg-II enhances mtROS and whether mtROS is involved in stimulation of cancer cell proliferation and migration remain unclear. METHODS AND RESULTS: Here, we show that ablation of arg-ii suppresses cell growth, migration, nuclear deformation, and DNA damage in melanoma cells. Vice versa, overexpression of arg-ii in melanoma cells promotes melanoma cell growth and migration accompanied by enhanced nuclear deformation and DNA damage. Ablation or overexpression of arg-ii reduces or enhances mtROS, respectively, accounting for the effects of Arg-II on melanoma growth, migration, and DNA damage. Further data demonstrate that Arg-II enhances mtROS through decreasing Sirtuin 3 (Sirt3) levels. Silencing sirt3 promotes melanoma growth, migration, nuclear deformation, and DNA damage through enhancing mtROS. In supporting of these findings, overexpression of sirt3 prevented Arg-II-induced mtROS production with concomitant prevention of Arg-II-induced cell growth, migration, nuclear deformation and DNA damage. Furthermore, we show that upregulation of Arg-II under hypoxia induces nuclear deformation and DNA damage through suppressing Sirt3. Similar results are obtained in A549 human lung carcinoma cells. In addition, analysis of publicly accessible datasets reveals that elevated arg-ii mRNA levels in human tumor samples including skin cutaneous melanoma and lung cancers associate with poorer prognosis. CONCLUSION: Altogether, our findings demonstrate a critical role of Arg-II-Sirt3-mtROS cascade in promoting melanoma growth, migration, nuclear deformation, and DNA damage linking to melanoma progression and malignancy, which could be therapeutic targets for cancers such as melanoma and lung carcinoma.