title: Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death.
abstract: Blockade of fatty acid synthase (FASN), a key enzyme involved in de novo lipogenesis, results in robust death of ovarian cancer cells. However, known FASN inhibitors have proven to be poor therapeutic agents due to their ability to induce cachexia. Therefore, we sought to identify additional targets in the pathway linking FASN inhibition and cell death whose modulation might kill ovarian cancer cells without the attendant side effects. Here, we show that the initiator caspase-2 is required for robust death of ovarian cancer cells induced by FASN inhibitors. REDD1 (also known as Rtp801 or DDIT4), a known mTOR inhibitor previously implicated in the response to FASN inhibition, is a novel caspase-2 regulator in this pathway. REDD1 induction is compromised in ovarian cancer cells that do not respond to FASN inhibition. Inhibition of FASN induced an ATF4-dependent transcriptional induction of REDD1; downregulation of REDD1 prevented orlistat-induced activation of caspase-2, as monitored by its cleavage, proteolytic activity and dimerization. Abrogation of REDD1-mediated suppression of mTOR by TSC2 RNAi protected FASN inhibitor-sensitive ovarian cancer cells (OVCA420 cells) from orlistat-induced death. Conversely, suppression of mTOR with the chemical inhibitors PP242 or rapamycin-sensitized DOV13, an ovarian cancer cell line incapable of inducing REDD1, to orlistat-induced cell death through caspase-2. These findings indicate that REDD1 positively controls caspase-2-dependent cell death of ovarian cancer cells by inhibiting mTOR, placing mTOR as a novel upstream regulator of caspase-2 and supporting the possibility of manipulating mTOR to enhance caspase-2 activation in ovarian cancer.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: C-S
authors.initials: CS
authors.lastname: Yang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Matsuura
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: N-J
authors.initials: NJ
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Robeson
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: B
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kornbluth
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D053143:Caspase 2 / Q000737:chemistry / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D000077403:Orlistat; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D034622:RNA Interference; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: C497109:ATF4 protein, human; C469991:DDIT4 protein, human; D004791:Enzyme Inhibitors; D007783:Lactones; C000624653:TSC2 protein, human; D014157:Transcription Factors; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051701:Activating Transcription Factor 4; D000077403:Orlistat; D064429:Fatty Acid Synthases; D058570:TOR Serine-Threonine Kinases; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases