The principal cause of cancer mortality is the dissemination of cells from the primary tumor to form distant metastases. The potential for a cell to migrate and invade depends on a multitude of signaling pathways, which present novel targets for anti-cancer therapies. Reactive oxygen species (ROS) have increasingly been implicated as modulators of tumorigenicity and many cancer types exhibit elevated ROS levels. An important regulatory enzyme of Redox balance is the mitochondrially expressed manganese superoxide dismutase (Sod2), which catalyzes the conversion of superoxide anion to hydrogen peroxide (H2O2). Elevated Sod2 expression has been described in a variety of invasive cancers including those of breast, brain and bladder. We have shown that Sod2 overexpression, and a concomitant increase in H2O2, can lead to a more metastatic and migratory behavior of fibrosarcoma HT-1080 cells. In this proposal we hope to elucidate how an increase in Sod2 expression and a surge in mitochondrial H2O2 production leads to this pro-migratory phenotype. To address this we will determine the spatial localization and site of action of mitochondrial H2O2, using novel Redox sensing green fluorescing protein probes. This will indicate if ROS can be targeted to specific areas within a moving cell, where they may carry out their role as second messengers. A novel role for ROS in cellular signaling is the oxidation and inactivation of protein tyrosine phosphatases, including those that are involved in the dynamic rearrangement of focal contacts at the plasma membrane by focal adhesion kinase. Using biochemical approaches we will investigate whether expression of Sod2 can significantly enhance pro-migratory focal adhesion kinase signaling via enhanced oxidation/inactivation of phosphatases that normally inhibit this pathway. Finally, we will investigate the role of anti-oxidant molecules in reversing the pro-migratory phenotype and signaling events of Sod2 expressing cells, both in vivo and in vitro. This will determine the validity of antioxidant based therapies for cancers that display an enhanced ROS burden due to elevated Sod2 expression. The studies of this proposal aim to address the hypothesize that elevated Sod2 expression results in the spatial inactivation of protein tyrosine phosphatases via increased mitochondrial H2O2 production, leading to pro-migratory signaling and an enhancement of the metastatic potential of cancer cells. This research will further our knowledge of the intracellular mechanisms that regulate metastasis. Understanding the role of reactive oxygen species in these events will aid in the development of novel antioxidant based cancer therapies.
| Hempel, Nadine; Bartling, Toni R; Mian, Badar et al. (2013) Acquisition of the metastatic phenotype is accompanied by H2O2-dependent activation of the p130Cas signaling complex. Mol Cancer Res 11:303-12 |
| Hempel, Nadine; Carrico, Pauline M; Melendez, J Andres (2011) Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis. Anticancer Agents Med Chem 11:191-201 |
