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The polyamines regulate endothelial cell survival during hypoxic stress through PI3K/AKT and MCL-1.

Kucharzewska, Paulina LU ; Welch, Johanna LU ; Svensson, Katrin LU and Belting, Mattias LU (2009) In Biochemical and Biophysical Research Communications 380(2). p.413-418
Abstract
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,... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochemical and Biophysical Research Communications
volume
380
issue
2
pages
413 - 418
publisher
Elsevier
external identifiers
  • WOS:000263742200039
  • PMID:19250631
  • Scopus:60349121139
ISSN
1090-2104
DOI
10.1016/j.bbrc.2009.01.097
language
English
LU publication?
yes
id
11d46aca-5917-4910-8224-854f96329ccb (old id 1368137)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19250631?dopt=Abstract
date added to LUP
2009-04-03 12:31:44
date last changed
2016-11-06 04:26:46
@misc{11d46aca-5917-4910-8224-854f96329ccb,
  abstract     = {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.},
  author       = {Kucharzewska, Paulina and Welch, Johanna and Svensson, Katrin and Belting, Mattias},
  issn         = {1090-2104},
  language     = {eng},
  number       = {2},
  pages        = {413--418},
  publisher    = {ARRAY(0xaaa3668)},
  series       = {Biochemical and Biophysical Research Communications},
  title        = {The polyamines regulate endothelial cell survival during hypoxic stress through PI3K/AKT and MCL-1.},
  url          = {http://dx.doi.org/10.1016/j.bbrc.2009.01.097},
  volume       = {380},
  year         = {2009},
}