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Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1

Doxorubicin is used extensively for chemotherapy of diverse types of cancer, yet the mechanism through which it inhibits proliferation of cancer cells remains unclear. Here we report that doxorubicin stimulates de novo synthesis of ceramide, which in turn activates CREB3L1, a transcription factor sy...

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Detalles Bibliográficos
Autores principales: Denard, Bray, Lee, Ching, Ye, Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524649/
https://www.ncbi.nlm.nih.gov/pubmed/23256041
http://dx.doi.org/10.7554/eLife.00090
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author Denard, Bray
Lee, Ching
Ye, Jin
author_facet Denard, Bray
Lee, Ching
Ye, Jin
author_sort Denard, Bray
collection PubMed
description Doxorubicin is used extensively for chemotherapy of diverse types of cancer, yet the mechanism through which it inhibits proliferation of cancer cells remains unclear. Here we report that doxorubicin stimulates de novo synthesis of ceramide, which in turn activates CREB3L1, a transcription factor synthesized as a membrane-bound precursor. Doxorubicin stimulates proteolytic cleavage of CREB3L1 by Site-1 Protease and Site-2 Protease, allowing the NH(2)-terminal domain of CREB3L1 to enter the nucleus where it activates transcription of genes encoding inhibitors of the cell cycle, including p21. Knockdown of CREB3L1 mRNA in human hepatoma Huh7 cells and immortalized human fibroblast SV589 cells conferred increased resistance to doxorubicin, whereas overexpression of CREB3L1 in human breast cancer MCF-7 cells markedly enhanced the sensitivity of these cells to doxorubicin. These results suggest that measurement of CREB3L1 expression may be a useful biomarker in identifying cancer cells sensitive to doxorubicin. DOI: http://dx.doi.org/10.7554/eLife.00090.001
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spelling pubmed-35246492012-12-19 Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1 Denard, Bray Lee, Ching Ye, Jin eLife Biochemistry Doxorubicin is used extensively for chemotherapy of diverse types of cancer, yet the mechanism through which it inhibits proliferation of cancer cells remains unclear. Here we report that doxorubicin stimulates de novo synthesis of ceramide, which in turn activates CREB3L1, a transcription factor synthesized as a membrane-bound precursor. Doxorubicin stimulates proteolytic cleavage of CREB3L1 by Site-1 Protease and Site-2 Protease, allowing the NH(2)-terminal domain of CREB3L1 to enter the nucleus where it activates transcription of genes encoding inhibitors of the cell cycle, including p21. Knockdown of CREB3L1 mRNA in human hepatoma Huh7 cells and immortalized human fibroblast SV589 cells conferred increased resistance to doxorubicin, whereas overexpression of CREB3L1 in human breast cancer MCF-7 cells markedly enhanced the sensitivity of these cells to doxorubicin. These results suggest that measurement of CREB3L1 expression may be a useful biomarker in identifying cancer cells sensitive to doxorubicin. DOI: http://dx.doi.org/10.7554/eLife.00090.001 eLife Sciences Publications, Ltd 2012-12-18 /pmc/articles/PMC3524649/ /pubmed/23256041 http://dx.doi.org/10.7554/eLife.00090 Text en Copyright © 2012, Denard et al http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry
Denard, Bray
Lee, Ching
Ye, Jin
Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1
title Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1
title_full Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1
title_fullStr Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1
title_full_unstemmed Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1
title_short Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1
title_sort doxorubicin blocks proliferation of cancer cells through proteolytic activation of creb3l1
topic Biochemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524649/
https://www.ncbi.nlm.nih.gov/pubmed/23256041
http://dx.doi.org/10.7554/eLife.00090
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