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HIV-Tat protein transduction domain specifically attenuates growth of polyamine deprived tumor cells.

Mani, Katrin LU ; Sandgren, Staffan LU ; Welch, Johanna LU ; Cheng, Fang LU ; Svensson, Katrin LU ; Persson, Lo LU and Belting, Mattias LU (2007) In Molecular Cancer Therapeutics 6(2). p.782-788
Abstract
Polyamines are essential for tumor cell growth, and the polyamine pathway represents an attractive target for cancer treatment. Several polyamine transport proteins have been cloned and characterized in bacteria and yeast cells; however, the mechanism of polyamine entry into mammalian cells remains poorly defined, although a role for proteoglycans has been suggested. Here, we show that the HIV-Tat transduction peptide, which is known to enter cells via a proteoglycan-dependent pathway, efficiently inhibits polyamine uptake. Polyamine uptake–deficient mutant cells with intact proteoglycan biosynthesis (CHO MGBG) displayed unperturbed HIV-Tat uptake activity compared with wild-type cells, supporting the notion that HIV-Tat peptide interferes... (More)
Polyamines are essential for tumor cell growth, and the polyamine pathway represents an attractive target for cancer treatment. Several polyamine transport proteins have been cloned and characterized in bacteria and yeast cells; however, the mechanism of polyamine entry into mammalian cells remains poorly defined, although a role for proteoglycans has been suggested. Here, we show that the HIV-Tat transduction peptide, which is known to enter cells via a proteoglycan-dependent pathway, efficiently inhibits polyamine uptake. Polyamine uptake–deficient mutant cells with intact proteoglycan biosynthesis (CHO MGBG) displayed unperturbed HIV-Tat uptake activity compared with wild-type cells, supporting the notion that HIV-Tat peptide interferes with polyamine uptake via competition for proteoglycan binding sites rather than a putative downstream transporter. HIV-Tat specifically inhibited growth of human carcinoma cells made dependent on extracellular polyamines by treatment with the polyamine biosynthesis inhibitor {alpha}-difluoromethylornithine; accordingly, the Tat peptide prevented intracellular accumulation of exogenous polyamines. Moreover, combined treatment with {alpha}-difluoromethylornithine and HIV-Tat efficiently blocked tumor growth in an experimental mouse model. We conclude that HIV-Tat transduction domain and polyamines enter cells through a common pathway, which can be used to target polyamine-dependent tumor growth in the treatment of cancer. (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
Molecular Cancer Therapeutics
volume
6
issue
2
pages
782 - 788
publisher
American Association for Cancer Research
external identifiers
  • wos:000244262700039
  • scopus:33847350814
ISSN
1538-8514
DOI
10.1158/1535-7163.MCT-06-0370
language
English
LU publication?
yes
id
d3a1dc39-7f26-44cd-8ae8-51f30ac16897 (old id 165619)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17308074&dopt=Abstract
date added to LUP
2007-07-17 13:27:16
date last changed
2017-01-01 05:08:51
@article{d3a1dc39-7f26-44cd-8ae8-51f30ac16897,
  abstract     = {Polyamines are essential for tumor cell growth, and the polyamine pathway represents an attractive target for cancer treatment. Several polyamine transport proteins have been cloned and characterized in bacteria and yeast cells; however, the mechanism of polyamine entry into mammalian cells remains poorly defined, although a role for proteoglycans has been suggested. Here, we show that the HIV-Tat transduction peptide, which is known to enter cells via a proteoglycan-dependent pathway, efficiently inhibits polyamine uptake. Polyamine uptake–deficient mutant cells with intact proteoglycan biosynthesis (CHO MGBG) displayed unperturbed HIV-Tat uptake activity compared with wild-type cells, supporting the notion that HIV-Tat peptide interferes with polyamine uptake via competition for proteoglycan binding sites rather than a putative downstream transporter. HIV-Tat specifically inhibited growth of human carcinoma cells made dependent on extracellular polyamines by treatment with the polyamine biosynthesis inhibitor {alpha}-difluoromethylornithine; accordingly, the Tat peptide prevented intracellular accumulation of exogenous polyamines. Moreover, combined treatment with {alpha}-difluoromethylornithine and HIV-Tat efficiently blocked tumor growth in an experimental mouse model. We conclude that HIV-Tat transduction domain and polyamines enter cells through a common pathway, which can be used to target polyamine-dependent tumor growth in the treatment of cancer.},
  author       = {Mani, Katrin and Sandgren, Staffan and Welch, Johanna and Cheng, Fang and Svensson, Katrin and Persson, Lo and Belting, Mattias},
  issn         = {1538-8514},
  language     = {eng},
  number       = {2},
  pages        = {782--788},
  publisher    = {American Association for Cancer Research},
  series       = {Molecular Cancer Therapeutics},
  title        = {HIV-Tat protein transduction domain specifically attenuates growth of polyamine deprived tumor cells.},
  url          = {http://dx.doi.org/10.1158/1535-7163.MCT-06-0370},
  volume       = {6},
  year         = {2007},
}