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Ornithine decarboxylase and extracellular polyamines regulate microvascular sprouting and actin cytoskeleton dynamics in endothelial cells.

Kucharzewska, Paulina LU ; Welch, Johanna LU ; Svensson, Katrin LU and Belting, Mattias LU (2010) In Experimental Cell Research 316. p.2683-2691
Abstract
The polyamines are essential for cancer cell proliferation during tumorigenesis. Targeted inhibition of ornithine decarboxylase (ODC), i.e. a key enzyme of polyamine biosynthesis, by alpha-difluoromethylornithine (DFMO) has shown anti-neoplastic activity in various experimental models. This activity has mainly been attributed to the anti-proliferative effect of DFMO in cancer cells. Here, we provide evidence that unperturbed ODC activity is a requirement for proper microvessel sprouting ex vivo as well as the migration of primary human endothelial cells. DFMO-mediated ODC inhibition was reversed by extracellular polyamine supplementation, showing that anti-angiogenic effects of DFMO were specifically related to polyamine levels. ODC... (More)
The polyamines are essential for cancer cell proliferation during tumorigenesis. Targeted inhibition of ornithine decarboxylase (ODC), i.e. a key enzyme of polyamine biosynthesis, by alpha-difluoromethylornithine (DFMO) has shown anti-neoplastic activity in various experimental models. This activity has mainly been attributed to the anti-proliferative effect of DFMO in cancer cells. Here, we provide evidence that unperturbed ODC activity is a requirement for proper microvessel sprouting ex vivo as well as the migration of primary human endothelial cells. DFMO-mediated ODC inhibition was reversed by extracellular polyamine supplementation, showing that anti-angiogenic effects of DFMO were specifically related to polyamine levels. ODC inhibition was associated with an abnormal morphology of the actin cytoskeleton during cell spreading and migration. Moreover, our data suggest that de-regulated actin cytoskeleton dynamics in DFMO treated endothelial cells may be related to constitutive activation of the small GTPase CDC42, i.e. a well-known regulator of cell motility and actin cytoskeleton remodeling. These insights into the potential role of polyamines in angiogenesis should stimulate further studies testing the combined anti-tumor effect of polyamine inhibition and established anti-angiogenic therapies in vivo. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Cell Research
volume
316
pages
2683 - 2691
publisher
Academic Press
external identifiers
  • wos:000281305800015
  • pmid:20594968
  • scopus:77955847340
ISSN
1090-2422
DOI
10.1016/j.yexcr.2010.05.033
language
English
LU publication?
yes
id
9273ee98-6900-4adb-9454-727398810b0d (old id 1645325)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20594968?dopt=Abstract
date added to LUP
2010-08-02 10:44:29
date last changed
2018-05-29 10:23:10
@article{9273ee98-6900-4adb-9454-727398810b0d,
  abstract     = {The polyamines are essential for cancer cell proliferation during tumorigenesis. Targeted inhibition of ornithine decarboxylase (ODC), i.e. a key enzyme of polyamine biosynthesis, by alpha-difluoromethylornithine (DFMO) has shown anti-neoplastic activity in various experimental models. This activity has mainly been attributed to the anti-proliferative effect of DFMO in cancer cells. Here, we provide evidence that unperturbed ODC activity is a requirement for proper microvessel sprouting ex vivo as well as the migration of primary human endothelial cells. DFMO-mediated ODC inhibition was reversed by extracellular polyamine supplementation, showing that anti-angiogenic effects of DFMO were specifically related to polyamine levels. ODC inhibition was associated with an abnormal morphology of the actin cytoskeleton during cell spreading and migration. Moreover, our data suggest that de-regulated actin cytoskeleton dynamics in DFMO treated endothelial cells may be related to constitutive activation of the small GTPase CDC42, i.e. a well-known regulator of cell motility and actin cytoskeleton remodeling. These insights into the potential role of polyamines in angiogenesis should stimulate further studies testing the combined anti-tumor effect of polyamine inhibition and established anti-angiogenic therapies in vivo.},
  author       = {Kucharzewska, Paulina and Welch, Johanna and Svensson, Katrin and Belting, Mattias},
  issn         = {1090-2422},
  language     = {eng},
  pages        = {2683--2691},
  publisher    = {Academic Press},
  series       = {Experimental Cell Research},
  title        = {Ornithine decarboxylase and extracellular polyamines regulate microvascular sprouting and actin cytoskeleton dynamics in endothelial cells.},
  url          = {http://dx.doi.org/10.1016/j.yexcr.2010.05.033},
  volume       = {316},
  year         = {2010},
}