Oncotarget

Research Papers:

Inhibition of SREBP1 sensitizes cells to death ligands

Yanina Eberhard, Marcela Gronda, Rose Hurren, Alessandro Datti, Neil MacLean, Troy Ketela, Jason Moffat, Jeffrey L. Wrana and Aaron D. Schimmer _

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2011; 2:186-196. https://doi.org/10.18632/oncotarget.239

Metrics: PDF 2730 views  |   HTML 4892 views  |   ?  


Abstract

Yanina Eberhard1, Marcela Gronda1, Rose Hurren1, Alessandro Datti2,3, Neil MacLean1, Troy Ketela4, Jason Moffat4, Jeffrey L. Wrana2, Aaron D. Schimmer1

1Princess Margaret Hospital, Ontario Cancer Institute, Toronto, ON, Canada

2Mount Sinai Hospital, Toronto, ON, Canada

3Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy

4Department of Molecular Genetics, Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON, Canada

Keywords: death receptor pathway of caspase activation, FASL, TRAIL, SREBP1, Orlistat

Received: January 10, 2011; Accepted: March 10, 2011; Published: March 10, 2011;

Correspondence:

Aaron D. Schimmer, e-mail:

Abstract

Evasion of death receptor ligand-induced apoptosis contributs to cancer development and progression. To better understand mechanisms conferring resistance to death ligands, we screened an siRNA library to identify sequences that sensitize resistant cells to fas activating antibody (CH-11). From this screen, we identified the Sterol-Regulatory Element-Binding Protein 1 (SREBP1), a transcription factor, which regulates genes involved in cholesterol and fatty acid synthesis including fatty acid synthase. Inhibition of SREBP1 sensitized PPC-1 and HeLa to the death receptor ligands CH-11 and TRAIL. In contrast, DU145 prostate cancer cells that are resistant to death ligands despite expressing the receptors on their cell surface remained resistant to CH-11 and TRAIL after knockdown of SREBP1. Consistent with the effects on cell viability, the addition of CH-11 activated caspases 3 and 8 in HeLa but not DU145 cells with silenced SREBP1. We demonstrated that knockdown of SREBP1 produced a marked decrease in fatty acid synthase expression. Furthermore, genetic or chemical inhibition of fatty acid synthase with shRNA or orlistat, respectively, recapitulated the effects of SREBP1 inhibition and sensitized HeLa but not DU145 cells to CH-11 and TRAIL. Sensitization to death receptor ligands by inhibition of fatty acid synthase was associated with activation of caspase 8 prior to caspase 9. Neither silencing of SREBP1 or fatty acid synthase changed basal expression of the core death receptor components Fas, caspase 8, FADD, caspase 3 or FLIP. Thus, inhibition of SREBP1 or its downstream target fatty acid synthase sensitizes resistant cells to death ligands.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 239