Expression and modification of ARC (apoptosis repressor with a CARD domain) is distinctly regulated by oxidative stress in cancer cells

Apoptosis repressor with a CARD domain (ARC), which has been shown to protect against oxidative stress-induced apoptosis, was initially found to be highly expressed in terminally differentiated tissues like heart and skeletal muscle. Recently, we and others have found that ARC is also expressed at high levels in multiple cancer tissues and cell lines. Here, we compared the regulation of ARC in response to oxidative stress between cancer cells and other types of cells. Similar to cardiomyocyte cell line H9c2 cells, cancer cells with reduced ARC expression were significantly more sensitive to oxidative stress. However, oxidative stress did not down-regulate ARC expression in cancer cells as it did in H9c2 cells. We further found that in H9c2 cells oxidative stress regulates ARC protein expression post-translationally through proteasome-mediated degradation. In cancer cell line HeLa, the majority of ARC exists in phosphorylated state in the absence of oxidative stress, whereas in H9c2 cells only marginal amount of ARC was phosphorylated under similar conditions. Our data suggest that the high level of ARC protein and the constitutive phosphorylation of ARC in cancer cells may play an important role in the protection of cancer cells against oxidative stress.