The polyamines regulate endothelial cell survival during hypoxic stress through PI3K/AKT and MCL-1.
Hypoxia-dependent angiogenesis is an inherent feature of solid tumors, and a better understanding of the molecular mechanisms of hypoxic cell-death should provide additional targets for cancer therapy. Here, we show a novel role of the polyamines in endothelial cell (EC) survival during hypoxia. Polyamine depletion by specific inhibition of ornithine decarboxylase was shown to protect ECs from hypoxia-induced apoptosis. Inhibition of the polyamines resulted in a significant induction of PI3K/AKT and its down-stream target MCL-1, i.e. an anti-apoptotic member of the BCL-2 family. Specific inhibitors of PI3K reversed the decrease of hypoxia-induced apoptosis as well as the induction of MCL-1 in polyamine-deprived cells. Moreover, siRNA-mediated down-regulation of MCL-1 was found to counter-act the protective effect of polyamine inhibition. We conclude that the polyamines regulate hypoxia-induced apoptosis in ECs through PI3K/AKT and MCL-1 dependent pathways. Our results may have important implications for the modulation of hypoxia-driven neovascularization.
Kucharzewska
Paulina
P
Department of Clinical Sciences, Section of Oncology, Lund University, Barngatan 2:1, 221 85 Lund, Sweden.
Welch
Johanna E
JE
Svensson
Katrin J
KJ
Belting
Mattias
M
D017209:Apoptosis; D015317:Biogenic Polyamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015687:Cell Hypoxia; D002470:Cell Survival; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
D015317:Biogenic Polyamines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt