Our observation that nuclear but not cytoplasmic
Our observation that nuclear, but not cytoplasmic EP4 expression is associated with different outcomes is interesting. In breast cancer, using the same methods, we did not detect EP4 in the nucleus of malignant Cytarabine whereas cytoplasmic EP4 was commonly observed . While G protein-coupled receptors are commonly observed at the plasma membrane, there is a growing body of evidence that nuclear EP receptors have important functions. EP4 has been detected in a perinuclear or nuclear location of porcine cerebral microvascular endothelial cells where it affects gene transcription through a pertussis toxin-sensitive mechanism . While there is evidence that EP4 contributes to malignant behavior in many cancers, the subcellular location and the mechanism underlying these linkages may be context dependent. Thus, cytoplasmic EP4 may drive breast cancer progression whereas nuclear EP4 may drive lung cancer, albeit by a different mechanism. Future studies will be required to understand the mechanism underlying the relationship between nuclear EP4 and poor outcomes in LANSCLC.
Novel, orally active selective EP4 antagonists are being developed and tested including AAT-007, which has been evaluated in humans for its analgesic properties . Efficacy and safety in normal volunteers and osteoarthritis associated pain have been established in two U.S. trials. However, efficacy has not been assessed in cancer models or in cancer clinical trials. Our institution will commence the first trial evaluating this drug as a potential antineoplastic in the coming year.
Acknowledgements Supported by the P.J. Aldridge Foundation, Veterans Administration Merit Award 101BX000169 and NCI P30 CA134274.
Introduction Elevated plasma cholesterol levels are associated with an increased risk for the development of atherosclerosis and other metabolic diseases . Therefore, elimination of excess cholesterol is an effective strategy to lessen the risk of these illnesses. Cholesterol lowering can be achieved in the body by impairing intestinal cholesterol absorption, reducing cholesterol synthesis or increasing cholesterol disposal through enhancement of synthesis and elimination of bile acids . Cholesterol homeostasis in mammals is maintained by a well-balanced control between supply and catabolism of cholesterol . Supply of cholesterol includes hepatic de novo synthesis and intestinal absorption; these two mechanisms are regulated reciprocally . Cholesterol in the body can be derived from de novo synthesis in the liver by the rate-limiting enzyme 3‑hydroxy‑3methylglutaryl coenzyme A reductase (HMGCR), whereas effective intestinal cholesterol absorption is governed by several key intestinal cholesterol transporter proteins, in particular the Niemann Pick C1-like 1 protein [5, 6]. Cholesterol can be directly eliminated into the intestine lumen through enterocytes . Though, hepatic conversion to bile acids remains as one of the predominant catabolic pathway for cholesterol, enabling the removal of excess lipid from the body. Therefore, bile acid synthesis is a crucial step in the maintenance of cholesterol homeostasis . The classic pathway for bile acid synthesis is initiated by hydroxylation of cholesterol at position 7 via the action of cholesterol 7α hydroxylase (CYP7A1), which is an endoplasmic reticulum localized enzyme . However, an “alternative” (or “acidic”) pathway involves hydroxylation of cholesterol at position 27 by the mitochondrial enzyme sterol 27 hydroxylase (CYP27A1) . The liver also plays a key role in cholesterol balance by influencing the inflow and the outflow of the lipid to and from the liver, respectively [9, 10]. Lipoprotein complexes, such as low density lipoprotein (LDL) transport insoluble cholesterol molecules in the circulation. Hepatocytes express LDL receptors on their cell surface, which bind to LDL complexes causing their endocytosis, and thus mediating clearance from the blood. Excess cholesterol can efflux from hepatocytes to apolipoprotein A1 acceptors through ATP-binding cassette transporters, including the ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), a key step in the formation of nascent high density lipoproteins (HDL) .