title: Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1.
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 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.
authors.affiliation: Department of Molecular Genetics ,  University of Texas Southwestern Medical Center ,  Dallas ,  United States.
authors.forename: Bray
authors.initials: B
authors.lastname: Denard
authors.forename: Ching
authors.initials: C
authors.lastname: Lee
authors.forename: Jin
authors.initials: J
authors.lastname: Ye
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D003412:Cricetulus; D017362:Cyclic AMP Response Element-Binding Protein / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; C485618:CREB3L1 protein, human; D002518:Ceramides; D017362:Cyclic AMP Response Element-Binding Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D004317:Doxorubicin; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human