Adnan Munkarah1, Ismail Mert2, Jasdeep Chhina3, Suhail Hamid4, Laila Poisson5, Sharon Hensley-Alford6, Shailendra Giri7, Ramandeep Rattan8. 1. 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. 2. Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA. Electronic address: imert@med.wayne.edu. 3. Department of Women's Health, Obstetrics and Gynecology, Henry Ford Hospital, USA. Electronic address: jchhina1@hfhs.org. 4. Department of Neurology, Henry Ford Hospital, USA. Electronic address: hsuhail1@hfhs.org. 5. Center for Bioinformatics, Henry Ford Hospital, USA; Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA. Electronic address: lpoisso1@hfhs.org. 6. Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA. Electronic address: salford1@hfhs.org. 7. 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. 8. 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.
Abstract
OBJECTIVES: 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. CONCLUSION: 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.
OBJECTIVES: 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. CONCLUSION: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: Riya Khetan; Cintya Dharmayanti; Todd A Gillam; Eric Kübler; Manuela Klingler-Hoffmann; Carmela Ricciardelli; Martin K Oehler; Anton Blencowe; Sanjay Garg; Hugo Albrecht Journal: Cancers (Basel) Date: 2022-05-10 Impact factor: 6.575