title: Targeting of free fatty acid receptor 1 in EOC: A novel strategy to restrict the adipocyte-EOC dependence.
abstract: OBJECTIVE
  Adipocyte derived free fatty acids (FFA) promote epithelial ovarian cancer (EOC) by acting as a fuel source to support the energy requirement of the cancer cells. FFA may also exert biological effects through signaling pathways. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified. Our objective was to investigate the role of FFAR/GPCRs in EOC and assess their potential as therapeutic targets.
  
  
  METHODS
  The mRNA (RT-PCR) expression of FFAR/GPCR family members (FFAR1/GPR40; FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120 and GPR84) was examined in: (1) a syngeneic mouse model of EOC fed high energy diet (60% fat) or regular diet (30% fat), (2) EOC cell lines exposed to free fatty acids and (3) specimens from 13 histologically normal ovaries and 28 high grade ovarian serous carcinomas. The GPR 40 antagonist, GW1100, was used to inhibit FFAR1/GPR40 and cell survival was assayed by MTT in various cell lines.
  
  
  RESULTS
  High Grade Serous carcinoma specimens expressed significantly increased GPR40 compared to normal ovaries (p=0.0020). Higher expression was noted in advanced stage disease. ID8 ovarian tumors from mice fed with high fat diet also showed higher GPR40 expression. Exposing EOC cells to FFAs, increased GPR40 expression. Treatment of EOC cell lines with GW100 resulted in growth inhibition and was associated with an alteration in their energy metabolism.
  
  
  CONCLUSIONS
  FFA-induced cancer cell growth may be partly mediated through FFAR1/GPR40. Targeting of FFAR1/GPR40 may be an attractive treatment strategy in EOC, and possibly offers a targeted treatment for a subset of EOC patients.
authors.affiliation: Department of Women's Health, Obstetrics and Gynecology, Henry Ford Hospital, USA; Josephine Ford Cancer Institute, Henry Ford Hospital, Detroit, MI, USA. Electronic address: amunkar1@hfhs.org.
authors.forename: Adnan
authors.initials: A
authors.lastname: Munkarah
authors.affiliation: Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA. Electronic address: imert@med.wayne.edu.
authors.forename: Ismail
authors.initials: I
authors.lastname: Mert
authors.affiliation: Department of Women's Health, Obstetrics and Gynecology, Henry Ford Hospital, USA. Electronic address: jchhina1@hfhs.org.
authors.forename: Jasdeep
authors.initials: J
authors.lastname: Chhina
authors.affiliation: Department of Neurology, Henry Ford Hospital, USA. Electronic address: hsuhail1@hfhs.org.
authors.forename: Suhail
authors.initials: S
authors.lastname: Hamid
authors.affiliation: Center for Bioinformatics, Henry Ford Hospital, USA; Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA. Electronic address: lpoisso1@hfhs.org.
authors.forename: Laila
authors.initials: L
authors.lastname: Poisson
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA. Electronic address: salford1@hfhs.org.
authors.forename: Sharon
authors.initials: S
authors.lastname: Hensley-Alford
authors.affiliation: Josephine Ford Cancer Institute, Henry Ford Hospital, Detroit, MI, USA; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA. Electronic address: sgiri1@hfhs.org.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Giri
authors.affiliation: Department of Women's Health, Obstetrics and Gynecology, Henry Ford Hospital, USA; Josephine Ford Cancer Institute, Henry Ford Hospital, Detroit, MI, USA. Electronic address: rrattan1@hfhs.org.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Rattan
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D004734:Energy Metabolism; D005260:Female; D006019:Glycolysis; D006801:Humans; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C473034:FFAR1 protein, human; C106262:FFAR3 protein, human; D043562:Receptors, G-Protein-Coupled