Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of Abbreviations: ACAT, acetoacetyl-CoA transferase; acetyl-CoA, acetyl-coenzyme A; Arp2/3, actin-related protein 2/3 (actin polymerizing complex) BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4. 0/). 14 W. Likus et al. / Drug Resistance Updates 25 (2016) 13-25 the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.
9 10 11 12 Running title: sNPF and DILP2 govern starvation-mediated hyperactivity and triglyceride 13 metabolism in fruit flies. 14 15 16 a AEK and HP contributed equally to this work.Abstract: 20 Circadian clock regulates various behavioral, metabolic and physiological processes to 21 occur at the most suitable time of the day. The most apparent behavioral outputs of the clock are 22 activity-rest rhythm and feeding. While clock regulates these two behaviors through 23 interconnected neuronal circuits, the precise pathway through which the clock coordinates 24 metabolism in accordance with the behavioral rhythms largely remains to be elucidated. This 25 study was aimed to elucidate the role of two circadian relevant metabolic neuropeptides, short 26 neuropeptide F (sNPF) and Drosophila Insulin Like Peptide 2 (DILP2) in triglyceride 27 metabolism, starvation-mediated hyperactivity, and food intake in Drosophila. The results 28 showed that snpf transcripts exhibit significant rhythmicity under 12:12 hour light-dark cycles 29 (LD) and constant darkness (DD). Knockdown of sNPF in sNPF producing neurons enhanced 30 the starvation-mediated hyperactivity in flies compared to the control. Further studies showed 31 that sNPF suppresses starvation-induced hyperactivity partly through the sNPF receptors 32 (sNPFR) expressed in insulin producing cells (IPC). Knockdown of Drosophila insulin like 33 peptide 2 (dilp2) in IPCs and reduced expression of the insulin receptors (InR) in the fat body 34 altered the starvation-mediated hyperactivity, lipid storage, and increased the food intake after 35 starvation. These results suggest a role for sNPF in modulating locomotor activity in accordance 36 with the nutrient availability and a novel role for circadian output molecule DILP2 in regulating 37 triglyceride metabolism and starvation-mediated behavioral changes in Drosophila. 38 39 triglyceride metabolism 40 41 42The circadian clock drives daily rhythms in a wide array of physiological and behavioral 43 processes by scheduling it at the appropriate time of the day. This inherent timekeeping system 44 coordinates the phase of two fundamental behavioral rhythms such as feeding and sleep/wake 45 cycles and it is believed to aid the organism to adapt with the cyclic external environmental 46 changes. The growing body of evidence indicates that the circadian clock not only mediates 47 optimal phasing of behavioral rhythmicity during 24 hour of a day but also has intimate ties with 48 metabolism [1]. While the clock orchestrates numerous metabolic pathways, the nutrient 49 availability and metabolic status can in turn feed back to impinge on the functioning of the 50 circadian clock [2], [3], [4], [5]. A large body of evidence accumulated over the past two 51 decades remarkably improved our understanding of the vital role of the clock in metabolism, 52 feeding behavior, and sleep wake cycle [6]. However, little is known about the precise 53 underlying pathways by which the circadian clock aids the organism to attain temporal 54 ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.