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:
https://lup.lub.lu.se/record/1595001
- author
- Aili, Ulrika
LU
; Johnsson, Richard
; Fransson, Lars-Åke
LU
; Ellervik, Ulf
and Mani, Katrin
LU
- organization
- publishing date
- 2010
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cancer Research
- volume
- 70
- issue
- 9
- pages
- 3771 - 3779
- publisher
- American Association for Cancer Research Inc.
- 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
- 2016-04-04 09:06:12
- date last changed
- 2023-10-17 22:50:31
@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 Inc.}},
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}},
doi = {{10.1158/0008-5472.CAN-09-4331}},
volume = {{70}},
year = {{2010}},
}