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  • FFAs are essential nutritional molecules that can also modul


    FFAs are essential nutritional molecules that can also modulate numerous cellular functions. Fatty 5-Methyl-CTP derivatives like prostaglandins, leukotrienes lysophosphatidic acid, spinhgosine-1-phosphate and others are well documented to carry out signal transduction via G-protein coupled receptors (GPCRs) [13], [14]. By being natural ligands for peroxisome activated receptors, they have a pivotal role in transcription of genes associated with lipid and glucose metabolism [15]. FFAs have been shown to act as growth factors by activating PI3K and EGFR pathways [16]. The cellular signaling seems to occur through a family of G-coupled cell surface receptors recently identified as free fatty acid receptors (FFARs) G-coupled cell surface receptors [16], [17]. These include FFAR1/GPR40, FFAR2/GPR43, FFAR3/GPR41 and FFAR4/GPR120 and GPR84. GPR41 and GPR43 are activated by short-chain-FFAs, while, GPR40 and GPR120 can be activated by medium- and long-chain-FFAs [16], [17]. Recently, activation or inhibition of FFFARs, especially FFAR1/GPR40 and FFAR4/GPR120 have been shown to modulate growth of breast [14], prostate [18], melanoma [19], pancreatic [20] and colon [21] cancer cells. Such evidence suggests that FFAs may orchestrate certain cellular pathways leading to cancer growth and spread by acting as extracellular signaling molecules. In this study, we aimed to investigate the expression and role of FFARs in EOC with their potential therapeutic targeting.
    Material and methods
    Discussion Obesity is the most significant health issue in the USA and also a significant global problem [27]. Results from the Ovarian Cancer Association Consortium which included 12,390 women with ovarian cancer showed that higher BMI is associated with adverse survival among the majority of women with ovarian cancer [28]. Recent laboratory studies have also demonstrated the intriguing relationship between adipocytes and EOC [2], [9], [10], [29]. The interaction between the two cell-populations involves several factors that include: 1) the energy requirements of cancer cells which is supplied by the FFAs released by adipocytes, 2) the inflammatory milieu created by adipocytes and that drives cancer cell growth, 3) and other growth factors present in the adipocyte secreted extracellular matrix [3]. However, the cellular cross-talk, that occurs at the molecular level between the FFAs and ovarian cancer cell, is not well studied. FFAs have been more commonly implicated in supporting ovarian cancer growth and metastasis by functioning as a fuel source to aid the mitochondrial respiration [10]. Those FFAs are first generated through lipolysis of lipids stored in the adipocytes by specific enzymes including hormone sensitive lipase, adipose triglyceride lipase, triacyl glycerol hydrolase and monoacyl glycerol lipase [30], [31]. They are then taken up the cancer cells by help of specific fatty acid uptake receptors including fatty acid transporter CD36, fatty acid binding proteins 1–6 and a family of solute carriers 27A1–6 [31]. Inside the cancer cell, the FFAs get incorporated into its metabolism or structural components [10], [31]. FFAs also actively participate in various biological processes by either acting as precursors of various signaling and structural molecules or acting themselves as signaling molecules as shown by the recent identification of an orphan G protein-coupled receptors family (FFARs/GPRs), that specifically responds to FFA ligands [16]. In the present study, we focused on the role of FFAs as signaling molecules and demonstrated for the first time that FFAs and one of their G-protein coupled receptor, namely FFAR1/GPR40, plays a significant role in ovarian cancer. FFAR1/GPR40 belongs to a class of previously orphan GPCRs, now identified as fatty acid receptors FFAR1-4 and GPR84 [16]. GPR40 is normally expressed in various tissues, with the highest expression observed in pancreatic beta-cells [32]. FFAR1/GPR40 acts as receptor for medium and long chain FFAs [16], [32]. Limited data is available about its expression patterns in cancer cells. Studies have reported increased expression in melanoma, neuroblastoma, breast, pancreatic, colonic, and endometrial cancer cells [14], [18], [19], [21], [33].