Decoy receptor DcR1 Is Induced in a p50/Bcl3-Dependent manner and attenuates the efficacy of temozolomide

Nassir M. Mansour, Giovanna M. Bernal, Longtao Wu, Clayton D. Crawley, Kirk E. Cahill, David J. Voce, Irina V. Balyasnikova, Wei Zhang, Ruben Spretz, Luis Nunez, Gustavo F. Larsen, Ralph R. Weichselbaum, Bakhtiar Yamini*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IkB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.

Original languageEnglish (US)
Pages (from-to)2039-2048
Number of pages10
JournalCancer Research
Volume75
Issue number10
DOIs
StatePublished - May 15 2015

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temozolomide
Receptors, Tumor Necrosis Factor, Member 10c
Glioma
CD95 Antigens
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mansour, N. M., Bernal, G. M., Wu, L., Crawley, C. D., Cahill, K. E., Voce, D. J., ... Yamini, B. (2015). Decoy receptor DcR1 Is Induced in a p50/Bcl3-Dependent manner and attenuates the efficacy of temozolomide. Cancer Research, 75(10), 2039-2048. https://doi.org/10.1158/0008-5472.CAN-14-2144
Mansour, Nassir M. ; Bernal, Giovanna M. ; Wu, Longtao ; Crawley, Clayton D. ; Cahill, Kirk E. ; Voce, David J. ; Balyasnikova, Irina V. ; Zhang, Wei ; Spretz, Ruben ; Nunez, Luis ; Larsen, Gustavo F. ; Weichselbaum, Ralph R. ; Yamini, Bakhtiar. / Decoy receptor DcR1 Is Induced in a p50/Bcl3-Dependent manner and attenuates the efficacy of temozolomide. In: Cancer Research. 2015 ; Vol. 75, No. 10. pp. 2039-2048.
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abstract = "Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IkB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.",
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Mansour, NM, Bernal, GM, Wu, L, Crawley, CD, Cahill, KE, Voce, DJ, Balyasnikova, IV, Zhang, W, Spretz, R, Nunez, L, Larsen, GF, Weichselbaum, RR & Yamini, B 2015, 'Decoy receptor DcR1 Is Induced in a p50/Bcl3-Dependent manner and attenuates the efficacy of temozolomide', Cancer Research, vol. 75, no. 10, pp. 2039-2048. https://doi.org/10.1158/0008-5472.CAN-14-2144

Decoy receptor DcR1 Is Induced in a p50/Bcl3-Dependent manner and attenuates the efficacy of temozolomide. / Mansour, Nassir M.; Bernal, Giovanna M.; Wu, Longtao; Crawley, Clayton D.; Cahill, Kirk E.; Voce, David J.; Balyasnikova, Irina V.; Zhang, Wei; Spretz, Ruben; Nunez, Luis; Larsen, Gustavo F.; Weichselbaum, Ralph R.; Yamini, Bakhtiar.

In: Cancer Research, Vol. 75, No. 10, 15.05.2015, p. 2039-2048.

Research output: Contribution to journalArticle

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T1 - Decoy receptor DcR1 Is Induced in a p50/Bcl3-Dependent manner and attenuates the efficacy of temozolomide

AU - Mansour, Nassir M.

AU - Bernal, Giovanna M.

AU - Wu, Longtao

AU - Crawley, Clayton D.

AU - Cahill, Kirk E.

AU - Voce, David J.

AU - Balyasnikova, Irina V.

AU - Zhang, Wei

AU - Spretz, Ruben

AU - Nunez, Luis

AU - Larsen, Gustavo F.

AU - Weichselbaum, Ralph R.

AU - Yamini, Bakhtiar

PY - 2015/5/15

Y1 - 2015/5/15

N2 - Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IkB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.

AB - Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IkB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.

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