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Targeted Oncology

, Volume 11, Issue 6, pp 763–769 | Cite as

Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines

  • Weiya Z. Wysham
  • Dario R. Roque
  • Jianjun Han
  • Lu Zhang
  • Hui Guo
  • Paola A. Gehrig
  • Chunxiao ZhouEmail author
  • Victoria L. Bae-JumpEmail author
Original Research Article

Abstract

Objective

Fatty acid synthase (FAS) is a key lipogenic enzyme that is highly expressed in endometrial cancer. Orlistat is a weight loss medication that has been shown to be a potent inhibitor of FAS. The goal of this study was to evaluate the anti-tumorigenic potential of orlistat in endometrial cancer cell lines.

Methods

The endometrial cancer cell lines ECC-1 and KLE were used. Cell proliferation was assessed by MTT assay after treatment with orlistat. Cell cycle progression was evaluated by Cellometer and apoptosis was assessed using the Annexin V assay. Reactive oxygen species (ROS) was measured using the DCFH-DA assay. Western immunoblotting was performed to determine changes in FAS, cellular stress, cell cycle progression, and the AMPK/mTOR pathways.

Results

Orlistat inhibited cell proliferation by 61 % in ECC-1 cells and 57 % in KLE cells at a dose of 500 μM. Treatment with orlistat at this concentration resulted in G1 arrest (p < 0.05) but did not affect apoptosis. Orlistat increased ROS and induced the expression of BIP (1.28-fold in ECC-1 compared to control, p < 0.05; 1.92-fold in KLE, p < 0.05) and PERK (2.25-fold in ECC-1, 1.4-fold in KLE, p < 0.05). Western immunoblot analysis demonstrated that orlistat decreased expression of important proteins in fatty acid metabolism including FAS (67 % in ECC-1, 15 % in KLE), acetyl-CoA carboxylase (40 % in ECC-1, 35 % in KLE), and carnitine palmitoyltransferase 1A (CPT1A) (65 % in ECC-1, 25 % in KLE) in a dose-dependent manner. In addition, orlistat at a dose of 500 μM increased expression of phosphorylated-AMPK (1.9-fold in ECC-1, p < 0.01; 1.5-fold in KLE, p < 0.05) and decreased expression of phosphorylated-Akt (25 % in ECC-1, p < 0.05; 37 % in KLE, p < 0.05) and phosphorylated-S6 (68 % in ECC-1, 56 % in KLE).

Conclusions

Orlistat inhibits cell growth in endometrial cancer cell lines through inhibition of fatty acid metabolism, induction of cell cycle G1 arrest, activation of AMPK and inhibition of the mTOR pathway. Given that patients with endometrial cancer have high rates of obesity, orlistat should be further investigated as a novel strategy for endometrial cancer treatment.

Keywords

Endometrial Cancer Endometrial Carcinoma Orlistat Endometrial Cancer Cell Cerulenin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with Ethical Standards

We certify that the manuscript represents valid work and has not been previously published or being considered for publication elsewhere. All authors have met authorship criteria. This work was generously supported by NIH/NCI 1K23CA143154-01A1 and the Steelman Fund.

Conflict of Interest

The authors, Weiya Z. Wysham, Dario R. Roque, Jianjun Han, Lu Zhang, Hui Guo, Paola A. Gehrig, Chunxiao Zhou, Victoria L. Bae-Jump, have no conflicts of interest to disclose.

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Weiya Z. Wysham
    • 1
  • Dario R. Roque
    • 1
  • Jianjun Han
    • 1
    • 2
  • Lu Zhang
    • 1
    • 3
  • Hui Guo
    • 1
    • 3
  • Paola A. Gehrig
    • 1
    • 4
  • Chunxiao Zhou
    • 1
    • 4
    Email author
  • Victoria L. Bae-Jump
    • 1
    • 4
    Email author
  1. 1.Division of Gynecologic Oncology, Department of Obstetrics and GynecologyUniversity of North CarolinaChapel HillUSA
  2. 2.Department of Surgical OncologyShandong Cancer Hospital and InstituteJinanChina
  3. 3.Department of Gynecologic OncologyShandong Cancer Hospital and InstituteJinanChina
  4. 4.Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA

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