Inhibition of Fatty-acid Synthase Induces Caspase-8-mediated Tumor Cell Apoptosis by Up-regulating DDIT4

Jeffrey W. Smith,Andrei Osterman,Lynn M. Knowles,Chen Yang

doi:10.1074/jbc.m803384200

Abstract

Fatty-acid synthase (FAS) is up-regulated in a broad range of cancers, including those of the breast, prostate, and ovaries. In tumor cells, the inhibition of FAS elicits cell cycle arrest and apoptosis, so it is considered a potential drug target for oncology. Results from this study show that inhibition of FAS, by either knockdown with small interfering RNA or inhibition with the small molecule drug orlistat, leads to activation of the receptor-mediated apoptotic cascade (caspase-8-mediated) and ultimately to cell death. However, knockdown of two enzymes upstream of FAS, acetyl-CoA carboxylase-alpha and ATP-citrate lyase, fails to activate caspase-8 or to elicit apoptosis in tumor cells, even though palmitate synthesis was suppressed. Using differential gene analysis, we traced the unique apoptotic effect of FAS inhibition to up-regulation of DDIT4 (DNA damage-inducible transcript 4), a stress-response gene that negatively regulates the mTOR pathway. These findings indicate that suppression of palmitate synthesis is not sufficient for eliciting tumor cell death and suggest that the unique effect of inhibition of FAS results from negative regulation of the mTOR pathway via DDIT4.

Highlights

Eukaryotic fatty-acid synthase (FAS)2 synthesizes palmitate, the precursor of long chain fatty acids [1]
These findings indicate that suppression of palmitate biosynthesis alone is not sufficient to elicit tumor cell death and reveal that inhibition of FAS has effects on tumor cells that extend beyond lipid biosynthesis
Apoptosis—RNA interference was used to silence the expression of FAS, ACC-␣, and ATP-citrate lyase (ACL) and to assess their effects on apoptosis in a panel of tumor cells lines (MDA-MB-435 and MCF-7 mammary carcinoma cells and LNCaP and PC-3 prostate cancer cells)

Summary

Introduction

Eukaryotic fatty-acid synthase (FAS)2 synthesizes palmitate, the precursor of long chain fatty acids [1]. Knockdown of two enzymes upstream of FAS, acetyl-CoA carboxylase-␣ and ATP-citrate lyase, fails to activate caspase-8 or to elicit apoptosis in tumor cells, even though palmitate synthesis was suppressed.

Results

Conclusion