The mechanisms underlying the inhibitory effects of n

The mechanisms underlying the inhibitory effects of n-3 FAs on neoplasia have not been completely elucidated. Until recently, the emphasis has been on the ability of n-3 FAs to compete for the pathways that lead to the synthesis of pro-inflammatory eicosanoids from arachidonic acid, an n-6 FA, thereby reducing eicosanoid levels [4] and generating anti-inflammatory mediators [5]. However, it is now clear that n-3 FAs exert many of their effects through two G-protein-coupled receptors (GPCRs), FFA1 and FFA4. These GPCRs are activated by long-chain polyunsaturated fatty acids that act as agonist ligands. This finding has led to the development of selective agonists for free fatty Copanlisib receptors (FFARs), focusing on their potential value in the treatment of metabolic disease as well as inflammation [6], [7], [8], [9]. The roles of FFARs in cancer cells have only recently been examined [10]. This report describes a study that examined the roles of FFARs in ovarian cancer cells. Specifically, the ability of FFAR agonists to inhibit proliferation induced by lysophosphatidic acid (LPA) and epidermal growth factor (EGF) was investigated. The EGF receptor (EGFR) has been studied as a therapeutic target in ovarian cancer [11], [12], [13]. LPA generation and LPA receptors (LPARs) have also been identified as important targets for therapeutic inhibition in ovarian cancer [14], [15], [16], [17]. Some of the responses to LPA that may contribute to ovarian tumor progression include enhanced migration [18] and epithelial to mesenchymal transition [19]. Furthermore, there is evidence for crucial positive cross-talk between LPARs and the EGFR, as previously demonstrated by our group for prostate cancer cells [20], [21] and breast cancer cells [22]. These findings have raised the hypothesis that FFAR agonists interfere with EGF action by inhibiting LPAR-mediated events. The studies presented herein address these topics in ovarian cancer cell lines.
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Introduction Heart failure (HF) affects approximately 5.7 million people in the U.S. at an annual cost of nearly 30 billion dollars, and this is estimated to increase to nearly 9 million people at a cost of nearly 80 billion dollars by 2030 [1]. Despite a well-defined pharmacological therapeutic regimen that includes β-adrenergic receptor blockers, angiotensin converting enzyme inhibitor/angiotensin receptor blockers, diuretics, and aldosterone antagonists, the five-year mortality rate is still greater than 50% [1]. Furthermore, the mortality rate for HF has not declined in years, highlighting the unmet need for new therapeutic options. Omega-3 polyunsaturated fatty acids (ω3-PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are important regulators of cardiovascular health [2], [3]. Several clinical trials have demonstrated that ω3-PUFAs confer a survival benefit in coronary heart disease (CHD) by preventing sudden death [4], [5], [6], [7], [8], and more recently clinical trials have indicated that ω3-PUFAs might improve outcomes in HF [9], [10], [11], [12], [13]. Despite these potential benefits, the use of ω3-PUFAs in CHD and HF remains controversial.
ω3-PUFAs in HF, a potential new therapeutic target
ω3-PUFAs and the case for an EPA-therapeutic index
The potential of Ffar4 signaling as a novel mechanism of ω3-PUFA cardioprotective signaling A major impediment to establishing a benefit for ω3-PUFAs in HF or any other CVD is the lack of a clearly defined molecular mechanism that delineates how increased ω3-PUFA levels confer cardioprotection. In that regard, our prior findings indicate that EPA prevents fibrosis in a mouse model of pressure overload-induced HF, but is not accumulated in cardiac myocyte or fibroblast membranes. Although incorporation into cellular membranes is considered the classic mechanism of action for ω3-PUFAs, the failure of cardiac myocytes and fibroblasts to accumulate EPA suggests an alternate mechanism. In the last 10years, a family of orphan G-protein coupled receptors (GPR) have been classified as receptors for free fatty acids (FFA). GPR41 and GPR43, now Ffar3 and Ffar2, were identified as receptors for short-chain FA (<8 carbons) [61], GPR84, which is unclassified, was identified as a receptor for medium chain FA (9-14 carbons) [62], and GPR40 and GPR120, now Ffar1 and Ffar4, were identified as receptors for long-chain FA [63], [64]. The identification of the Ffar family uncovers an entirely novel mechanism of action for FA signaling.