Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1

Bray Denard, Ching Lee, Jin Ye

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

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 NH2-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.

Original languageEnglish (US)
Article numbere00090
JournaleLife
Volume2012
Issue number1
DOIs
StatePublished - Dec 18 2012

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Doxorubicin
Chemical activation
Cells
Cell Proliferation
Neoplasms
Gene encoding
Chemotherapy
Ceramides
MCF-7 Cells
Biomarkers
Transcription
Fibroblasts
Hepatocellular Carcinoma
Cell Cycle
Peptide Hydrolases
Transcription Factors
Breast Neoplasms
Membranes
Drug Therapy
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1. / Denard, Bray; Lee, Ching; Ye, Jin.

In: eLife, Vol. 2012, No. 1, e00090, 18.12.2012.

Research output: Contribution to journalArticle

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