VEGF-C protects prostate cancer cells from oxidative stress by the activation of mTORC-2 and AKT-1
M. H. Muders, H. Zheng1, G.B. Baretton, E. Wang1, D.J. Tindall1, K. Datta1
Institut für Pathologie, Universitätsklinikum Dresden
1Department of Urology, Mayo Clinic, Rochester, MN, USA
Aims: Recurrence and subsequent metastatic transformation of cancer develops from a subset of malignant cells, which show the ability to resist stress and to adopt to a changing microenvironment. Long-term therapeutic success can only be achieved by identifying and targeting signalling cascades that help these cells to survive during stress. Here, we evaluate the role of the lymphangiogenic growth factor VEGF-C in reactive oxygen stress resistance of prostate cancer cells in vitro.
Methods: To induce reactive oxygen stress in prostate cancer we added hydrogen peroxide to cancer cells in vitro. Cell death was measured by immunoflourescence (PI staining). Immunoblot was used to detect the activation status of Akt and its downstream molecules. Immunoprecipitation experiments detected the status of mTOR Complex 2.
Results: We have discovered that VEGF-C acts directly on prostate cancer cells to protect them against oxidative stress. VEGF-C increased the survival of prostate cancer cells during hydrogen peroxide stress by the activation of AKT-1/PKBα. This activation was mediated by mTOR complex 2. Finally, the transmembrane non-tyrosine kinase receptor Neuropilin-2 was found to be essential for the VEGF-C-mediated AKT activation.
Conclusions: Our findings suggest a novel function of VEGF-C in protecting cancer cells from stress-induced cell death. This is different from the known function of VEGF-C in lymphangiogenesis.