Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release

Moon Taek Park, Min Jung Kim, Young Hee Kang, Soon Young Choi, Jae Hoon Lee, Jung A. Choi, Chang Mo Kang, Chul Koo Cho, Seong Man Kang, Sangwoo Bae, Yun Sil Lee, Hee Yong Chung, Su Jae Lee

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

The use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic effect on cancer by overcoming a high apoptotic threshold. Here, we showed that phytosphingosine treatment in combination with γ-radiation enhanced apoptotic cell death of radiation-resistant human T-cell lymphoma in a caspase-independent manner. Combination treatment induced an increase in intracellular reactive oxygen species (ROS) level, mitochondrial relocalization of B-cell lymphoma-2(Bcl-2)- associated X protein (Bax), poly-adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) activation, and nuclear translocation of apoptosis-inducing factor (AIF). siRNA targeting of AIF effectively protected cells from the combination treatment-induced cell death. An antioxidant, N-acetyl-L-cysteine (NAC), inhibited Bax relocalization and AIF translocation but not PARP-1 activation. Moreover, transfection of Bax-siRNA significantly inhibited AIF translocation. Pretreatment of PARP-1 inhibitor, DPQ (3,4-dihydro-5-[4-(1-piperidinyl)-butoxy]- 1(2H)-isoquinolinone), or PARP-1-siRNA also partially attenuated AIF translocation, whereas the same treatment did not affect intracellular ROS level and Bax redistribution. Taken together, these results demonstrate that enhancement of cell death of radiation-resistant cancer cells by phytosphingosine treatment in combination with γ-radiation is mediated by nuclear translocation of AIF, which is in turn mediated both by ROS-dependent Bax relocalization and ROS-independent PARP-1 activation. The molecular signaling pathways that we elucidated in this study may provide potential drug targets for radiation sensitization of cancers refractive to radiation therapy.

Original languageEnglish
Pages (from-to)1724-1733
Number of pages10
JournalBlood
Volume105
Issue number4
DOIs
Publication statusPublished - 2005 Feb 15

Fingerprint

phytosphingosine
Apoptosis Inducing Factor
Ionizing radiation
Cell death
Ionizing Radiation
bcl-2-Associated X Protein
Reactive Oxygen Species
Cell Death
Cells
Radiation
Small Interfering RNA
Neoplasms
Chemical activation
Poly Adenosine Diphosphate Ribose
Therapeutics
T-cells
Poly(ADP-ribose) Polymerases
T-Cell Lymphoma
Radiotherapy
Acetylcysteine

ASJC Scopus subject areas

  • Hematology

Cite this

Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release. / Park, Moon Taek; Kim, Min Jung; Kang, Young Hee; Choi, Soon Young; Lee, Jae Hoon; Choi, Jung A.; Kang, Chang Mo; Cho, Chul Koo; Kang, Seong Man; Bae, Sangwoo; Lee, Yun Sil; Chung, Hee Yong; Lee, Su Jae.

In: Blood, Vol. 105, No. 4, 15.02.2005, p. 1724-1733.

Research output: Contribution to journalArticle

Park, MT, Kim, MJ, Kang, YH, Choi, SY, Lee, JH, Choi, JA, Kang, CM, Cho, CK, Kang, SM, Bae, S, Lee, YS, Chung, HY & Lee, SJ 2005, 'Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release', Blood, vol. 105, no. 4, pp. 1724-1733. https://doi.org/10.1182/blood-2004-07-2938
Park, Moon Taek ; Kim, Min Jung ; Kang, Young Hee ; Choi, Soon Young ; Lee, Jae Hoon ; Choi, Jung A. ; Kang, Chang Mo ; Cho, Chul Koo ; Kang, Seong Man ; Bae, Sangwoo ; Lee, Yun Sil ; Chung, Hee Yong ; Lee, Su Jae. / Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release. In: Blood. 2005 ; Vol. 105, No. 4. pp. 1724-1733.
@article{d56e9a7840d44924906e8e5e397b2b2c,
title = "Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release",
abstract = "The use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic effect on cancer by overcoming a high apoptotic threshold. Here, we showed that phytosphingosine treatment in combination with γ-radiation enhanced apoptotic cell death of radiation-resistant human T-cell lymphoma in a caspase-independent manner. Combination treatment induced an increase in intracellular reactive oxygen species (ROS) level, mitochondrial relocalization of B-cell lymphoma-2(Bcl-2)- associated X protein (Bax), poly-adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) activation, and nuclear translocation of apoptosis-inducing factor (AIF). siRNA targeting of AIF effectively protected cells from the combination treatment-induced cell death. An antioxidant, N-acetyl-L-cysteine (NAC), inhibited Bax relocalization and AIF translocation but not PARP-1 activation. Moreover, transfection of Bax-siRNA significantly inhibited AIF translocation. Pretreatment of PARP-1 inhibitor, DPQ (3,4-dihydro-5-[4-(1-piperidinyl)-butoxy]- 1(2H)-isoquinolinone), or PARP-1-siRNA also partially attenuated AIF translocation, whereas the same treatment did not affect intracellular ROS level and Bax redistribution. Taken together, these results demonstrate that enhancement of cell death of radiation-resistant cancer cells by phytosphingosine treatment in combination with γ-radiation is mediated by nuclear translocation of AIF, which is in turn mediated both by ROS-dependent Bax relocalization and ROS-independent PARP-1 activation. The molecular signaling pathways that we elucidated in this study may provide potential drug targets for radiation sensitization of cancers refractive to radiation therapy.",
author = "Park, {Moon Taek} and Kim, {Min Jung} and Kang, {Young Hee} and Choi, {Soon Young} and Lee, {Jae Hoon} and Choi, {Jung A.} and Kang, {Chang Mo} and Cho, {Chul Koo} and Kang, {Seong Man} and Sangwoo Bae and Lee, {Yun Sil} and Chung, {Hee Yong} and Lee, {Su Jae}",
year = "2005",
month = "2",
day = "15",
doi = "10.1182/blood-2004-07-2938",
language = "English",
volume = "105",
pages = "1724--1733",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "4",

}

TY - JOUR

T1 - Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release

AU - Park, Moon Taek

AU - Kim, Min Jung

AU - Kang, Young Hee

AU - Choi, Soon Young

AU - Lee, Jae Hoon

AU - Choi, Jung A.

AU - Kang, Chang Mo

AU - Cho, Chul Koo

AU - Kang, Seong Man

AU - Bae, Sangwoo

AU - Lee, Yun Sil

AU - Chung, Hee Yong

AU - Lee, Su Jae

PY - 2005/2/15

Y1 - 2005/2/15

N2 - The use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic effect on cancer by overcoming a high apoptotic threshold. Here, we showed that phytosphingosine treatment in combination with γ-radiation enhanced apoptotic cell death of radiation-resistant human T-cell lymphoma in a caspase-independent manner. Combination treatment induced an increase in intracellular reactive oxygen species (ROS) level, mitochondrial relocalization of B-cell lymphoma-2(Bcl-2)- associated X protein (Bax), poly-adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) activation, and nuclear translocation of apoptosis-inducing factor (AIF). siRNA targeting of AIF effectively protected cells from the combination treatment-induced cell death. An antioxidant, N-acetyl-L-cysteine (NAC), inhibited Bax relocalization and AIF translocation but not PARP-1 activation. Moreover, transfection of Bax-siRNA significantly inhibited AIF translocation. Pretreatment of PARP-1 inhibitor, DPQ (3,4-dihydro-5-[4-(1-piperidinyl)-butoxy]- 1(2H)-isoquinolinone), or PARP-1-siRNA also partially attenuated AIF translocation, whereas the same treatment did not affect intracellular ROS level and Bax redistribution. Taken together, these results demonstrate that enhancement of cell death of radiation-resistant cancer cells by phytosphingosine treatment in combination with γ-radiation is mediated by nuclear translocation of AIF, which is in turn mediated both by ROS-dependent Bax relocalization and ROS-independent PARP-1 activation. The molecular signaling pathways that we elucidated in this study may provide potential drug targets for radiation sensitization of cancers refractive to radiation therapy.

AB - The use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic effect on cancer by overcoming a high apoptotic threshold. Here, we showed that phytosphingosine treatment in combination with γ-radiation enhanced apoptotic cell death of radiation-resistant human T-cell lymphoma in a caspase-independent manner. Combination treatment induced an increase in intracellular reactive oxygen species (ROS) level, mitochondrial relocalization of B-cell lymphoma-2(Bcl-2)- associated X protein (Bax), poly-adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) activation, and nuclear translocation of apoptosis-inducing factor (AIF). siRNA targeting of AIF effectively protected cells from the combination treatment-induced cell death. An antioxidant, N-acetyl-L-cysteine (NAC), inhibited Bax relocalization and AIF translocation but not PARP-1 activation. Moreover, transfection of Bax-siRNA significantly inhibited AIF translocation. Pretreatment of PARP-1 inhibitor, DPQ (3,4-dihydro-5-[4-(1-piperidinyl)-butoxy]- 1(2H)-isoquinolinone), or PARP-1-siRNA also partially attenuated AIF translocation, whereas the same treatment did not affect intracellular ROS level and Bax redistribution. Taken together, these results demonstrate that enhancement of cell death of radiation-resistant cancer cells by phytosphingosine treatment in combination with γ-radiation is mediated by nuclear translocation of AIF, which is in turn mediated both by ROS-dependent Bax relocalization and ROS-independent PARP-1 activation. The molecular signaling pathways that we elucidated in this study may provide potential drug targets for radiation sensitization of cancers refractive to radiation therapy.

UR - http://www.scopus.com/inward/record.url?scp=13544276189&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=13544276189&partnerID=8YFLogxK

U2 - 10.1182/blood-2004-07-2938

DO - 10.1182/blood-2004-07-2938

M3 - Article

C2 - 15486061

AN - SCOPUS:13544276189

VL - 105

SP - 1724

EP - 1733

JO - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -