TY - JOUR TI - Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1 AU - Denard, Bray AU - Lee, Ching AU - Ye, Jin A2 - Davis, Roger VL - 1 PY - 2012 DA - 2012/12/18 SP - e00090 C1 - eLife 2012;1:e00090 DO - 10.7554/eLife.00090 UR - https://doi.org/10.7554/eLife.00090 AB - 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. KW - doxorubicin KW - cancer KW - CREB3L1 KW - ceramide JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -