Department of Women's Health, Obstetrics and Gynecology, Henry Ford Hospital, USA; Josephine Ford Cancer Institute, Henry Ford Hospital, Detroit, MI, USA.
Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA.
Gynecol Oncol. 2016 Apr;141(1):72-9. doi: 10.1016/j.ygyno.2016.02.026.
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.
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.
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.
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.
脂肪细胞衍生的游离脂肪酸 (FFA) 通过作为癌细胞的能量来源来促进卵巢上皮癌 (EOC)。FFA 还可以通过信号通路发挥生物学作用。最近，发现了一组 FFA 激活的 G 蛋白偶联受体 (FFAR/GPCR)。我们的目的是研究 FFAR/GPCR 在 EOC 中的作用，并评估它们作为治疗靶点的潜力。
在以下情况下检查了 FFAR/GPCR 家族成员（FFAR1/GPR40；FFAR2/GPR43、FFAR3/GPR41、FFAR4/GPR120 和 GPR84）的 mRNA（RT-PCR）表达：（1）接受高能量饮食（60%脂肪）或常规饮食（30%脂肪）的同源小鼠 EOC 模型；(2) 暴露于游离脂肪酸的 EOC 细胞系；(3) 来自 13 个组织学正常卵巢和 28 个高级别卵巢浆液性癌的标本。使用 GPR40 拮抗剂 GW1100 抑制 FFAR1/GPR40，并用 MTT 测定各种细胞系中的细胞存活。
高级别浆液性癌标本与正常卵巢相比，GPR40 表达显著增加 (p=0.0020)。晚期疾病中表达更高。高脂肪饮食喂养的小鼠 ID8 卵巢肿瘤也显示出更高的 GPR40 表达。将 FFA 暴露于 EOC 细胞会增加 GPR40 表达。GW100 处理 EOC 细胞系会导致生长抑制，并伴有能量代谢改变。
FFA 诱导的癌细胞生长可能部分通过 FFAR1/GPR40 介导。靶向 FFAR1/GPR40 可能是 EOC 的一种有吸引力的治疗策略，并可能为 EOC 患者的亚组提供靶向治疗。
