Abstract
Oxidative stress is known to cause tumorigenesis through induction of DNA and lipid damage. It also promotes tumor progression through a largely unknown mechanism. Sulfiredoxin (Srx) is an oxidation-induced antioxidant protein that catalyzes the reduction of hyperoxidized peroxiredoxins (Prxs) to the reduced form to restore their peroxidase activity. Our previous study demonstrates that Srx is a novel target of activator protein-1 (AP-1) activation and TAM67 (a dominant negative form of c-Jun) inhibition. However, the role of Srx in cell signaling and cancer development has not been well-studied. In this study, our goal is to investigate the function and molecular mechanism of Srx in human lung cancer.
Our current work demonstrates an important oncogenic role of Srx in cancer maintenance and progression through the Srx-Prx IV axis and the modulation of specific phosphokinase signaling cascades. First, tissue microarray was used to evaluate Srx expression in human primary lung cancer tissues. We found that Srx is highly expressed in lung squamous cell carcinoma and adenocarcinoma, but not in the normal lung. By knockdown of Srx in human lung cancer A549 cells, we discovered that Srx is required for anchorage independent colony formation, cell migration and invasion of A549 cells. Second, using immunoprecipitation and mass spectrometry, we identified proteins that interact with Srx. Surprisingly, we found that Prx IV was the predominant protein that interacts with Srx. Using purified recombinant proteins and surface plasmon resonance techniques, we demonstrated that Srx has a higher binding affinity to Prx IV than to other Prxs. Third, we found that knockdown of Prx IV, but not other Prxs, recapitulated the phenotypic outcomes of depleting Srx in A549 cells. In addition, when injected into SCID mice, disruption or enhancement of the Srx-Prx IV axis leads respectively to reduction or acceleration of mouse tumor growth and lung metastasis formation. Furthermore, proteome profiler phosphokinase assay revealed that activation of specific phosphokinase signaling cascades, including AP-1, CREB and MAPK signaling, was dependent on the integrity of the Srx-Prx IV axis. In summary, our findings demonstrate a novel oncogenic role of the Srx-Prx IV axis in human lung cancer, and suggest that targeting the Srx-Prx IV axis may provide novel effective strategies for cancer prevention and treatment.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A19.
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