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Attenuation of tumor growth by formation of antiproliferative glycosaminoglycans correlates with low acetylation of histone H3.

Aili, Ulrika LU ; Johnsson, Richard; Fransson, Lars-Åke LU ; Ellervik, Ulf and Mani, Katrin LU (2010) In Cancer Research 70(9). p.3771-3779
Abstract
Glycosaminoglycan (GAG) chains anchored to core proteins form proteoglycans, widely distributed cell-surface macromolecules with multiple functions, such as regulation of growth factor and cytokine signaling, cell-cell interactions, and uptake of biomolecules. The biosynthesis of GAG can be manipulated by xylosides attached to various hydrophobic groups, and we have earlier reported that a naphthoxyloside, 2-(6-hydroxynaphthyl) beta-D-xylopyranoside (XylNapOH), which serves as a primer for GAG synthesis, reduces tumor load up to 97% in vivo, despite lower efficiency in vitro. Here we show, using radiolabeled xylosides and coculture experiments, that XylNapOH-treated bladder and breast carcinoma cells secrete antiproliferative GAG chains... (More)
Glycosaminoglycan (GAG) chains anchored to core proteins form proteoglycans, widely distributed cell-surface macromolecules with multiple functions, such as regulation of growth factor and cytokine signaling, cell-cell interactions, and uptake of biomolecules. The biosynthesis of GAG can be manipulated by xylosides attached to various hydrophobic groups, and we have earlier reported that a naphthoxyloside, 2-(6-hydroxynaphthyl) beta-D-xylopyranoside (XylNapOH), which serves as a primer for GAG synthesis, reduces tumor load up to 97% in vivo, despite lower efficiency in vitro. Here we show, using radiolabeled xylosides and coculture experiments, that XylNapOH-treated bladder and breast carcinoma cells secrete antiproliferative GAG chains that are taken up by both normal and cancer cells and transported to the cell nuclei where they induce an antiproliferative effect, accompanied by apoptosis. We also show that XylNapOH treatment lowers the level of histone H3 acetylation selectively in bladder and breast carcinoma cells without affecting expression of histone H3. However, XylNapOH-primed GAG chains from normal cells are not internalized and do not cause growth retardation. Using in vitro and in vivo C6 glioma cell and tumor models, we show that XylNapOH is much more effective in vivo than in vitro. We propose that, in vivo, the antiproliferative XylNapOH-primed GAG chains produced by tumor cells inhibit tumor growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside prodrug, whereas no antiproliferative GAG chains are produced by surrounding normal cells. This is a novel mechanism for targeting tumor cells, making these xylosides promising drug candidates for antitumor therapy. (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
70
issue
9
pages
3771 - 3779
publisher
American Association for Cancer Research
external identifiers
  • wos:000278486200036
  • pmid:20406966
  • scopus:77951741986
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-09-4331
language
English
LU publication?
yes
id
db2f45c7-d93c-4214-a580-34dd68fd6def (old id 1595001)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20406966?dopt=Abstract
date added to LUP
2010-05-04 21:25:48
date last changed
2017-04-23 04:37:01
@article{db2f45c7-d93c-4214-a580-34dd68fd6def,
  abstract     = {Glycosaminoglycan (GAG) chains anchored to core proteins form proteoglycans, widely distributed cell-surface macromolecules with multiple functions, such as regulation of growth factor and cytokine signaling, cell-cell interactions, and uptake of biomolecules. The biosynthesis of GAG can be manipulated by xylosides attached to various hydrophobic groups, and we have earlier reported that a naphthoxyloside, 2-(6-hydroxynaphthyl) beta-D-xylopyranoside (XylNapOH), which serves as a primer for GAG synthesis, reduces tumor load up to 97% in vivo, despite lower efficiency in vitro. Here we show, using radiolabeled xylosides and coculture experiments, that XylNapOH-treated bladder and breast carcinoma cells secrete antiproliferative GAG chains that are taken up by both normal and cancer cells and transported to the cell nuclei where they induce an antiproliferative effect, accompanied by apoptosis. We also show that XylNapOH treatment lowers the level of histone H3 acetylation selectively in bladder and breast carcinoma cells without affecting expression of histone H3. However, XylNapOH-primed GAG chains from normal cells are not internalized and do not cause growth retardation. Using in vitro and in vivo C6 glioma cell and tumor models, we show that XylNapOH is much more effective in vivo than in vitro. We propose that, in vivo, the antiproliferative XylNapOH-primed GAG chains produced by tumor cells inhibit tumor growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside prodrug, whereas no antiproliferative GAG chains are produced by surrounding normal cells. This is a novel mechanism for targeting tumor cells, making these xylosides promising drug candidates for antitumor therapy.},
  author       = {Aili, Ulrika and Johnsson, Richard and Fransson, Lars-Åke and Ellervik, Ulf and Mani, Katrin},
  issn         = {1538-7445},
  language     = {eng},
  number       = {9},
  pages        = {3771--3779},
  publisher    = {American Association for Cancer Research},
  series       = {Cancer Research},
  title        = {Attenuation of tumor growth by formation of antiproliferative glycosaminoglycans correlates with low acetylation of histone H3.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-09-4331},
  volume       = {70},
  year         = {2010},
}