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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
; ; and
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
2016-04-04 09:24:42
date last changed
2022-01-29 17:43:56
@article{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    = {{Elsevier}},
  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}},
  doi          = {{10.1016/j.bbrc.2009.01.097}},
  volume       = {{380}},
  year         = {{2009}},
}