Manganese superoxide dismutase mediates anoikis resistance and tumor metastasis in nasopharyngeal carcinoma

Abstract

Metastatic cancer cells are able to survive the loss of attachment to the extracellular matrix (ECM) by developing resistance to anoikis, a specialized form of apoptosis. Here we investigated resistance to anoikis in nasopharyngeal carcinoma cells (NPC). When detached in culture, the highly metastatic S18 NPC cell line exhibited strong resistance to anoikis, as compared to the poorly metastatic S26 NPC cell line. With loss of attachment, S18 cells had lower levels of reactive oxygen species (ROS) and higher levels of manganese superoxide dismutase (MnSOD), an essential mitochondrial antioxidant enzyme. MnSOD knockdown increased the levels of ROS and diminished resistance to anoikis in S18 cells. Conversely, removal of reactive oxygen species (ROS) using NAC or overexpression of MnSOD in S26 cells induced resistance to anoikis. Blocking β-catenin through RNA interference down-regulated MnSOD expression and enhanced anoikis in S18 cells, while β-catenin overexpression enhanced MnSOD expression and suppressed anoikis in S26 cells. In addition, knockdown of MnSOD in S18 cells reduced colony formation in vitro and ameliorated lung metastasis in vivo. In patients with NPC, MnSOD expression was positively correlated with pathologic tumor stages and negatively correlated with overall survival. These results establish MnSOD as a key mediator of anoikis resistance and tumor metastasis and suggest that β-catenin/MnSOD could be a therapeutic target in NPC.