Matriptase Is A Reactive Oxygen Species (ROS) Biosensor that Contributes to ER-Negative Breast Cancer Proliferation And Migration
Johnson, Michael D
Matriptase is a type-II serine protease that is widely expressed in epithelial tissues and is known to play a role in normal epithelial cell integrity. Matriptase expression and activation are normally tightly regulated by its cognate inhibitor, Hepatocyte Growth Factor Activator Inhibitor-1, HAI-1, but is often dysregulated in many cancers and correlates with poor patient prognoses. Matriptase is known to act as an oncogene and has been shown to activate tumor promoting substrates such as uPA, PAR2 and pro-HGF. Matriptase activation correlates universally with inflammatory conditions such as low pH and has been shown to occur as a result of stimulation with compounds such as sphingosine 1-phosphate (S-1P) in A1N4 breast cancer cells. In this thesis, we have shown that EGFR-directed matriptase activation contributes to proliferation and migration in ER-negative breast cancer. In standard culture conditions, high level receptor tyrosine kinase and matriptase activation was detected by immunoblot in HER2+ SK-BR-3 and AU565, and MDA-MB-468 TNBC cells. Treatment of AU565, SK-BR-3, and HCC1569 Basal-like cells with EGF resulted in enhanced ErbB2 and EGFR phosphorylation, and increased matriptase activation, whereas serum starvation or dual EGFR/ErbB2 tyrosine kinase inhibitor, Lapatinib, treatment suppressed matriptase activation. ErbB2 inhibition with Mubritinib or clinically-used monoclonal antibodies, Trastuzumab and Pertuzumab had no effect on matriptase activation, whereas inhibition of EGFR activity decreased matriptase activation. We have also shown that matriptase is activated in Lapatinib-resistant SK-BR-3cells. Finally, we have demonstrated that ROS is central to the mechanism of matriptase activation and have used activated matriptase to direct N-acetyl cysteine (NAC) treatment in several carcinomas. This treatment resulted in cell death in all breast cancer subsets as well as pancreatic, lung, prostate, colon, stomach, and ovarian cancer. These data demonstrated the potential contribution of ROS-mediated survival, its independence of kinase-mediated survival, and that matriptase-directed NAC therapy could have significant clinical impact. This work is promising for the future clinical use of levels of shed species of matriptase as biomarkers for NAC, and potentially other antioxidant therapies as well as the study of matriptase in other ROS-dependent malignancies.
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