Human Noxin is an anti-apoptotic protein in response to DNA damage of A549 non-small cell lung carcinoma

Abstract

Human Noxin (hNoxin, C11Orf82), a homolog of mouse noxin, is highly expressed in colorectal and lung cancer tissues. hNoxin contains a DNA-binding C-domain in RPA1, which mediates DNA metabolic processes, such as DNA replication and DNA repair. Expression of hNoxin is associated with S phase in cancer cells and in normal cells. Expression of hNoxin was induced by ultraviolet (UV) irradiation. Knockdown of hNoxin caused growth inhibition of colorectal and lung cancer cells. The comet assay and western blot analysis revealed that hNoxin knockdown induced apoptosis through activation of p38 mitogen-activated protein kinase (MAPK)/p53 in non-small cell lung carcinoma A549 cells. Furthermore, simultaneous hNoxin knockdown and treatment with DNA-damaging agents, such as camptothecin (CPT) and UV irradiation, enhanced apoptosis, whereas Trichostatin A (TSA) did not. However, transient overexpression of hNoxin rescued cells from DNA damage-induced apoptosis but did not block apoptosis in the absence of DNA damage. These results suggest that hNoxin may be associated with inhibition of apoptosis in response to DNA damage. An adenovirus expressing a short hairpin RNA against hNoxin transcripts significantly suppressed the growth of A549 tumor xenografts, indicating that hNoxin knockdown has in vivo anti-tumor efficacy. Thus, hNoxin is a DNA damage-induced anti-apoptotic protein and potential therapeutic target in cancer. What's new Noxin was previously identified in mice as a stress-induced gene that may be an important component of the defense machinery of stressed cells. Here, the authors identified human Noxin as a novel cancer-specific gene whose expression is cell cycle-regulated and induced by ultraviolet radiation. Knockdown of hNoxin induced apoptosis of A549 cancer cells via p38 MAPK/p53 signaling. Overexpression of hNoxin suppressed DNA damage-induced apoptosis. These data suggest that hNoxin has anti-apoptotic activity that protects cancer cells against DNA damage. Knockdown of hNoxin reduced tumor growth in a mouse xenograft model, suggesting that hNoxin is a potential therapeutic target in cancer.