The roles of TGF-β3 and peroxynitrite in removal of hyper-radiosensitivity by priming irradiation

Nina Jeppesen Edin; Joe Alexander Sandvik; Chang Cheng; Linda Bergersen; Erik Olai Pettersen

doi:10.3109/09553002.2014.906767

The roles of TGF-β3 and peroxynitrite in removal of hyper-radiosensitivity by priming irradiation

Nina Jeppesen Edin, Joe Alexander Sandvik, Chang Cheng, Linda Bergersen, Erik Olai Pettersen

4 Citationer (Scopus)

Abstract

PURPOSE: To investigate the mechanisms inducing and maintaining the permanent elimination of low dose hyper-radiosensitivity (HRS) in cells given a dose of 0.3 Gy at low dose-rate (LDR) (0.3 Gy/h).

MATERIALS AND METHODS: Two human HRS-positive cell lines (T-47D, T98G) were used. The effects of pretreatments with transforming growth factor beta (TGF-β) neutralizers, TGF-β3 or peroxynitrite scavenger on HRS were investigated using the colony assay. Cytoplasmic levels of TGF-β3 were measured using post-embedding immunogold electron microscopic analysis.

RESULTS: TGF-β3 neutralizer inhibited the removal of HRS by LDR irradiation. Adding 0.001 ng/ml TGF-β3 to cells removed HRS in T98G cells while 0.01 ng/ml additionally induced resistance to higher doses. Cytoplasmic levels of TGF-β3 were higher in LDR-primed cells than in unirradiated cells. The presence of the peroxynitrite scavenger uric acid inhibited the effect of LDR irradiation. Furthermore, the permanent elimination of HRS in LDR-primed cells was reversed by treatment with uric acid. The removal of HRS by medium from hypoxic cells was inhibited by adding TGF-β3 neutralizer to the medium before transfer or by adding hypoxia inducible factor 1 (HIF-1) inhibitor chetomin to the cell medium during hypoxia.

CONCLUSIONS: TGF-β3 is involved in the regulation of cellular responses to small doses of acute irradiation. TGF-β3 activation seems to be induced by low dose-rate irradiation by a mechanism involving inducible nitric oxide (iNOS) and peroxynitrite, or during cycling hypoxia by a mechanism most likely involving HIF-1. The study suggests methods to turn resistance to doses in the HRS-range on (by TGF-β3) or off (by TGF-β3 neutralizer or by peroxynitrite inhibition).

Originalsprog	Engelsk
Tidsskrift	International Journal of Radiation Biology
Vol/bind	90
Udgave nummer	7
Sider (fra-til)	527-37
Antal sider	11
ISSN	0955-3002
DOI	https://doi.org/10.3109/09553002.2014.906767
Status	Udgivet - 2014
Udgivet eksternt	Ja

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10.3109/09553002.2014.906767

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@article{7cca91ab23f54c8da4e192629024d022,

title = "The roles of TGF-β3 and peroxynitrite in removal of hyper-radiosensitivity by priming irradiation",

abstract = "PURPOSE: To investigate the mechanisms inducing and maintaining the permanent elimination of low dose hyper-radiosensitivity (HRS) in cells given a dose of 0.3 Gy at low dose-rate (LDR) (0.3 Gy/h).MATERIALS AND METHODS: Two human HRS-positive cell lines (T-47D, T98G) were used. The effects of pretreatments with transforming growth factor beta (TGF-β) neutralizers, TGF-β3 or peroxynitrite scavenger on HRS were investigated using the colony assay. Cytoplasmic levels of TGF-β3 were measured using post-embedding immunogold electron microscopic analysis.RESULTS: TGF-β3 neutralizer inhibited the removal of HRS by LDR irradiation. Adding 0.001 ng/ml TGF-β3 to cells removed HRS in T98G cells while 0.01 ng/ml additionally induced resistance to higher doses. Cytoplasmic levels of TGF-β3 were higher in LDR-primed cells than in unirradiated cells. The presence of the peroxynitrite scavenger uric acid inhibited the effect of LDR irradiation. Furthermore, the permanent elimination of HRS in LDR-primed cells was reversed by treatment with uric acid. The removal of HRS by medium from hypoxic cells was inhibited by adding TGF-β3 neutralizer to the medium before transfer or by adding hypoxia inducible factor 1 (HIF-1) inhibitor chetomin to the cell medium during hypoxia.CONCLUSIONS: TGF-β3 is involved in the regulation of cellular responses to small doses of acute irradiation. TGF-β3 activation seems to be induced by low dose-rate irradiation by a mechanism involving inducible nitric oxide (iNOS) and peroxynitrite, or during cycling hypoxia by a mechanism most likely involving HIF-1. The study suggests methods to turn resistance to doses in the HRS-range on (by TGF-β3) or off (by TGF-β3 neutralizer or by peroxynitrite inhibition).",

keywords = "Cell Hypoxia/drug effects, Cell Line, Cell Survival/drug effects, Cytoplasm/drug effects, Humans, Nitric Oxide Synthase Type II/metabolism, Peroxynitrous Acid/pharmacology, Radiation Dosage, Radiation Tolerance/drug effects, Time Factors, Transforming Growth Factor beta3/pharmacology",

author = "Edin, {Nina Jeppesen} and Sandvik, {Joe Alexander} and Chang Cheng and Linda Bergersen and Pettersen, {Erik Olai}",

year = "2014",

doi = "10.3109/09553002.2014.906767",

language = "English",

volume = "90",

pages = "527--37",

journal = "International Journal of Radiation Biology",

issn = "0955-3002",

publisher = "Taylor & Francis",

number = "7",

}

TY - JOUR

T1 - The roles of TGF-β3 and peroxynitrite in removal of hyper-radiosensitivity by priming irradiation

AU - Edin, Nina Jeppesen

AU - Sandvik, Joe Alexander

AU - Cheng, Chang

AU - Bergersen, Linda

AU - Pettersen, Erik Olai

PY - 2014

Y1 - 2014

N2 - PURPOSE: To investigate the mechanisms inducing and maintaining the permanent elimination of low dose hyper-radiosensitivity (HRS) in cells given a dose of 0.3 Gy at low dose-rate (LDR) (0.3 Gy/h).MATERIALS AND METHODS: Two human HRS-positive cell lines (T-47D, T98G) were used. The effects of pretreatments with transforming growth factor beta (TGF-β) neutralizers, TGF-β3 or peroxynitrite scavenger on HRS were investigated using the colony assay. Cytoplasmic levels of TGF-β3 were measured using post-embedding immunogold electron microscopic analysis.RESULTS: TGF-β3 neutralizer inhibited the removal of HRS by LDR irradiation. Adding 0.001 ng/ml TGF-β3 to cells removed HRS in T98G cells while 0.01 ng/ml additionally induced resistance to higher doses. Cytoplasmic levels of TGF-β3 were higher in LDR-primed cells than in unirradiated cells. The presence of the peroxynitrite scavenger uric acid inhibited the effect of LDR irradiation. Furthermore, the permanent elimination of HRS in LDR-primed cells was reversed by treatment with uric acid. The removal of HRS by medium from hypoxic cells was inhibited by adding TGF-β3 neutralizer to the medium before transfer or by adding hypoxia inducible factor 1 (HIF-1) inhibitor chetomin to the cell medium during hypoxia.CONCLUSIONS: TGF-β3 is involved in the regulation of cellular responses to small doses of acute irradiation. TGF-β3 activation seems to be induced by low dose-rate irradiation by a mechanism involving inducible nitric oxide (iNOS) and peroxynitrite, or during cycling hypoxia by a mechanism most likely involving HIF-1. The study suggests methods to turn resistance to doses in the HRS-range on (by TGF-β3) or off (by TGF-β3 neutralizer or by peroxynitrite inhibition).

AB - PURPOSE: To investigate the mechanisms inducing and maintaining the permanent elimination of low dose hyper-radiosensitivity (HRS) in cells given a dose of 0.3 Gy at low dose-rate (LDR) (0.3 Gy/h).MATERIALS AND METHODS: Two human HRS-positive cell lines (T-47D, T98G) were used. The effects of pretreatments with transforming growth factor beta (TGF-β) neutralizers, TGF-β3 or peroxynitrite scavenger on HRS were investigated using the colony assay. Cytoplasmic levels of TGF-β3 were measured using post-embedding immunogold electron microscopic analysis.RESULTS: TGF-β3 neutralizer inhibited the removal of HRS by LDR irradiation. Adding 0.001 ng/ml TGF-β3 to cells removed HRS in T98G cells while 0.01 ng/ml additionally induced resistance to higher doses. Cytoplasmic levels of TGF-β3 were higher in LDR-primed cells than in unirradiated cells. The presence of the peroxynitrite scavenger uric acid inhibited the effect of LDR irradiation. Furthermore, the permanent elimination of HRS in LDR-primed cells was reversed by treatment with uric acid. The removal of HRS by medium from hypoxic cells was inhibited by adding TGF-β3 neutralizer to the medium before transfer or by adding hypoxia inducible factor 1 (HIF-1) inhibitor chetomin to the cell medium during hypoxia.CONCLUSIONS: TGF-β3 is involved in the regulation of cellular responses to small doses of acute irradiation. TGF-β3 activation seems to be induced by low dose-rate irradiation by a mechanism involving inducible nitric oxide (iNOS) and peroxynitrite, or during cycling hypoxia by a mechanism most likely involving HIF-1. The study suggests methods to turn resistance to doses in the HRS-range on (by TGF-β3) or off (by TGF-β3 neutralizer or by peroxynitrite inhibition).

KW - Cell Hypoxia/drug effects

KW - Cell Line

KW - Cell Survival/drug effects

KW - Cytoplasm/drug effects

KW - Humans

KW - Nitric Oxide Synthase Type II/metabolism

KW - Peroxynitrous Acid/pharmacology

KW - Radiation Dosage

KW - Radiation Tolerance/drug effects

KW - Time Factors

KW - Transforming Growth Factor beta3/pharmacology

U2 - 10.3109/09553002.2014.906767

DO - 10.3109/09553002.2014.906767

M3 - Journal article

C2 - 24650070

SN - 0955-3002

VL - 90

SP - 527

EP - 537

JO - International Journal of Radiation Biology

JF - International Journal of Radiation Biology

IS - 7

ER -

The roles of TGF-β3 and peroxynitrite in removal of hyper-radiosensitivity by priming irradiation

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