Advanced

Hypoxia-mediated induction of the polyamine system provides opportunities for tumor growth inhibition by combined targeting of vascular endothelial growth factor and ornithine decarboxylase.

Svensson, Katrin LU ; Welch, Johanna LU ; Kucharzewska, Paulina LU ; Bengtson, Per LU ; Bjurberg, Maria LU ; Påhlman, Sven LU ; Ten Dam, Gerdy B; Persson, Lo LU and Belting, Mattias LU (2008) In Cancer Research 68(22). p.9291-9301
Abstract
Hypoxia is a hallmark of solid tumors, which may offer opportunities for targeted therapies of cancer; however, the mechanisms that link hypoxia to malignant transformation and tumor progression are not fully understood. Here, we show that up-regulation of the polyamine system promotes cancer cell survival during hypoxic stress. Hypoxia was found to induce polyamine transport and the key enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC), in a variety of cancer cell lines. Increased ODC protein expression was shown in hypoxic, GLUT-1-expressing regions of tumor spheroids and experimental tumors, as well as in clinical tumor specimens. Hypoxic induction of the polyamine system was dependent on antizyme inhibitor (i.e., a key... (More)
Hypoxia is a hallmark of solid tumors, which may offer opportunities for targeted therapies of cancer; however, the mechanisms that link hypoxia to malignant transformation and tumor progression are not fully understood. Here, we show that up-regulation of the polyamine system promotes cancer cell survival during hypoxic stress. Hypoxia was found to induce polyamine transport and the key enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC), in a variety of cancer cell lines. Increased ODC protein expression was shown in hypoxic, GLUT-1-expressing regions of tumor spheroids and experimental tumors, as well as in clinical tumor specimens. Hypoxic induction of the polyamine system was dependent on antizyme inhibitor (i.e., a key positive regulator of ODC and polyamine transport), as shown by RNA interference experiments. Interestingly, depletion of the polyamines during hypoxia resulted in increased apoptosis, which indicates an essential role of the polyamines in cancer cell adaptation to hypoxic stress. These results were supported by experiments in an in vivo glioma tumor model, showing significantly enhanced antitumor effects of the antiangiogenic, humanized anti-vascular endothelial growth factor (VEGF) antibody bevacizumab when used in combination with the well-established, irreversible inhibitor of ODC, alpha-difluoromethylornithine. Our results provide important insights into the hypoxic stress response in malignant cells and implicate combined targeting of VEGF and ODC as an alternative strategy to treat cancer disease. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
68
issue
22
pages
9291 - 9301
publisher
American Association for Cancer Research
external identifiers
  • WOS:000261136600025
  • PMID:19010902
  • Scopus:56449109565
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-08-2340
language
English
LU publication?
yes
id
fd8bdce4-5dbc-4c5f-b465-4629b8f5e292 (old id 1271416)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19010902?dopt=Abstract
date added to LUP
2008-12-04 15:53:26
date last changed
2016-11-28 12:10:01
@misc{fd8bdce4-5dbc-4c5f-b465-4629b8f5e292,
  abstract     = {Hypoxia is a hallmark of solid tumors, which may offer opportunities for targeted therapies of cancer; however, the mechanisms that link hypoxia to malignant transformation and tumor progression are not fully understood. Here, we show that up-regulation of the polyamine system promotes cancer cell survival during hypoxic stress. Hypoxia was found to induce polyamine transport and the key enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC), in a variety of cancer cell lines. Increased ODC protein expression was shown in hypoxic, GLUT-1-expressing regions of tumor spheroids and experimental tumors, as well as in clinical tumor specimens. Hypoxic induction of the polyamine system was dependent on antizyme inhibitor (i.e., a key positive regulator of ODC and polyamine transport), as shown by RNA interference experiments. Interestingly, depletion of the polyamines during hypoxia resulted in increased apoptosis, which indicates an essential role of the polyamines in cancer cell adaptation to hypoxic stress. These results were supported by experiments in an in vivo glioma tumor model, showing significantly enhanced antitumor effects of the antiangiogenic, humanized anti-vascular endothelial growth factor (VEGF) antibody bevacizumab when used in combination with the well-established, irreversible inhibitor of ODC, alpha-difluoromethylornithine. Our results provide important insights into the hypoxic stress response in malignant cells and implicate combined targeting of VEGF and ODC as an alternative strategy to treat cancer disease.},
  author       = {Svensson, Katrin and Welch, Johanna and Kucharzewska, Paulina and Bengtson, Per and Bjurberg, Maria and Påhlman, Sven and Ten Dam, Gerdy B and Persson, Lo and Belting, Mattias},
  issn         = {1538-7445},
  language     = {eng},
  number       = {22},
  pages        = {9291--9301},
  publisher    = {ARRAY(0xaa5efc0)},
  series       = {Cancer Research},
  title        = {Hypoxia-mediated induction of the polyamine system provides opportunities for tumor growth inhibition by combined targeting of vascular endothelial growth factor and ornithine decarboxylase.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-08-2340},
  volume       = {68},
  year         = {2008},
}