Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1

Elife. 2012 Dec 18:1:e00090. doi: 10.7554/eLife.00090.


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:

Keywords: CREB3L1; Human; cancer; ceramide; doxorubicin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • CHO Cells
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Ceramides / metabolism
  • Cricetulus
  • Cyclic AMP Response Element-Binding Protein / agonists
  • Cyclic AMP Response Element-Binding Protein / genetics*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm / genetics
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Proprotein Convertases / genetics
  • Proprotein Convertases / metabolism
  • Proteolysis / drug effects
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Signal Transduction


  • Antibiotics, Antineoplastic
  • Biomarkers, Tumor
  • CREB3L1 protein, human
  • Ceramides
  • Cyclic AMP Response Element-Binding Protein
  • Cyclin-Dependent Kinase Inhibitor p21
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Doxorubicin
  • Proprotein Convertases
  • Serine Endopeptidases
  • membrane-bound transcription factor peptidase, site 1
  • Metalloendopeptidases
  • MBTPS2 protein, human