Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin complex-2 and AKT-1.
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. These tumor cells have distinctly different growth factor pathways and antiapoptotic responses compared with the vast majority of cancer cells. Long-term therapeutic success can only be achieved by identifying and targeting factors and signaling cascades that help these cells survive during stress. Both microarray and immunohistochemical analysis on human prostate cancer tissue samples have shown an increased expression of vascular endothelial growth factor-C (VEGF-C) in metastatic prostate cancer. 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/protein kinase Balpha. This activation was mediated by mammalian target of rapamycin complex-2 and was not observed in the absence of oxidative stress. Finally, the transmembrane nontyrosine kinase receptor neuropilin-2 was found to be essential for the VEGF-C-mediated AKT-1 activation. Indeed, our findings suggest a novel and distinct function of VEGF-C in protecting cancer cells from stress-induced cell death, thereby facilitating cancer recurrence and metastasis. This is distinctly different from the known function of VEGF-C in inducing lymphangiogenesis.
Muders
Michael H
MH
Department of Urologic Research, Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, Minnesota 55905, USA. muders.michael@mayo.edu
Zhang
Heyu
H
Wang
Enfeng
E
Tindall
Donald J
DJ
Datta
Kaustubh
K
D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D008297:Male; D039943:Neuropilin-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
C493245:CRTC2 protein, human; D039943:Neuropilin-2; D034741:RNA, Small Interfering; D014157:Transcription Factors; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D006861:Hydrogen Peroxide; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt