論文

査読有り
2015年6月

Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death

ONCOGENE
  • C-S Yang
  • ,
  • K. Matsuura
  • ,
  • N-J Huang
  • ,
  • A. C. Robeson
  • ,
  • B. Huang
  • ,
  • L. Zhang
  • ,
  • S. Kornbluth

34
25
開始ページ
3264
終了ページ
3272
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/onc.2014.271
出版者・発行元
NATURE PUBLISHING GROUP

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.

Web of Science ® 被引用回数 : 29

リンク情報
DOI
https://doi.org/10.1038/onc.2014.271
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/25151963
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340825
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000356592300005&DestApp=WOS_CPL
URL
http://europepmc.org/abstract/med/25151963
URL
http://orcid.org/0000-0003-4612-6031
ID情報
  • DOI : 10.1038/onc.2014.271
  • ISSN : 0950-9232
  • eISSN : 1476-5594
  • ORCIDのPut Code : 45669904
  • PubMed ID : 25151963
  • PubMed Central 記事ID : PMC4340825
  • Web of Science ID : WOS:000356592300005

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