Binding of Intracellular Myeloperoxidase to αV/β1 Integrin Serves as a Mechanism of Survival in Epithelial Ovarian Cancer

We were the first to report that epithelial ovarian cancer (EOC) cells and tissues express myeloperoxidase (MPO) that is known to play a role in immune surveillance and inflammation by myeloid cells. Additionally, we reported that MPO is colocalized with inducible nitric oxide synthase (iNOS), a key pro-oxidant enzyme, and plays a key role in regulating apoptosis in EOC cells. Whereas myeloid cells express MPO in a dimeric form, intriguingly, here we report the unique expression of only the monomeric form of MPO in EOC cells, tissues, and blood of an ovarian cancer patient. Additionally, we have identified a cell membrane receptor, alpha V/beta 1 integrin, that is uniquely expressed by both chemosensitive and chemoresistant EOC cells with significantly higher expression in chemoresistant EOC cells. More importantly, we have demonstrated that monoclonal antibodies against alpha V/beta 1 integrin induced cytotoxicity in EOC cells, but not in normal cells, that is also synergistic with conventional chemotherapies. Cytotoxicity of alpha V/beta 1 antibodies is due to conformational changes in alpha V/beta 1 integrin which prevents monomeric MPO binding to alpha V/beta 1 integrin inhibiting the activation of MPO, leading to increased apoptosis. Since normal epithelial cells and macrophages lack monomeric MPO and alpha V/beta 1 integrin system, targeting this unique MPO-dependent survival mechanism will selectively eliminate EOC cells and will be the target for developing specific ovarian cancer therapies.

Automated summary

We reported the expression of myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) in epithelial ovarian cancer (EOC) cells and tissues. We found that EOC cells express only the monomeric form of MPO, and identified the unique expression of cell membrane receptor alpha V/beta 1 integrin in both chemosensitive and chemoresistant EOC cells. Monoclonal antibodies against alpha V/beta 1 integrin induced cytotoxicity in EOC cells and showed synergy with conventional chemotherapies. Targeting this unique MPO-dependent survival mechanism may lead to specific ovarian cancer therapies.