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

Publication ,  Journal Article
Yang, C-S; Matsuura, K; Huang, N-J; Robeson, AC; Huang, B; Zhang, L; Kornbluth, S
Published in: Oncogene
June 2015

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.

Duke Scholars

Published In

Oncogene

DOI

EISSN

1476-5594

ISSN

0950-9232

Publication Date

June 2015

Volume

34

Issue

25

Start / End Page

3264 / 3272

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 2 Protein
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • RNA Interference
  • Protein Structure, Quaternary
  • Protein Multimerization
  • Ovarian Neoplasms
  • Orlistat
  • Oncology & Carcinogenesis
 

Citation

APA
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ICMJE
MLA
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Yang, C.-S., Matsuura, K., Huang, N.-J., Robeson, A. C., Huang, B., Zhang, L., & Kornbluth, S. (2015). Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death. Oncogene, 34(25), 3264–3272. https://doi.org/10.1038/onc.2014.271
Yang, C. -. S., K. Matsuura, N. -. J. Huang, A. C. Robeson, B. Huang, L. Zhang, and S. Kornbluth. “Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death.Oncogene 34, no. 25 (June 2015): 3264–72. https://doi.org/10.1038/onc.2014.271.
Yang C-S, Matsuura K, Huang N-J, Robeson AC, Huang B, Zhang L, et al. Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death. Oncogene. 2015 Jun;34(25):3264–72.
Yang, C. .. S., et al. “Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death.Oncogene, vol. 34, no. 25, June 2015, pp. 3264–72. Epmc, doi:10.1038/onc.2014.271.
Yang C-S, Matsuura K, Huang N-J, Robeson AC, Huang B, Zhang L, Kornbluth S. Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death. Oncogene. 2015 Jun;34(25):3264–3272.

Published In

Oncogene

DOI

EISSN

1476-5594

ISSN

0950-9232

Publication Date

June 2015

Volume

34

Issue

25

Start / End Page

3264 / 3272

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 2 Protein
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • RNA Interference
  • Protein Structure, Quaternary
  • Protein Multimerization
  • Ovarian Neoplasms
  • Orlistat
  • Oncology & Carcinogenesis