deregulated pathway
Recently Published Documents


TOTAL DOCUMENTS

7
(FIVE YEARS 1)

H-INDEX

3
(FIVE YEARS 0)

Author(s):  
Peter S. Coleman ◽  
Risa A. Parlo

Interpreting connections between the multiple networks of cell metabolism is indispensable for understanding how cells maintain homeostasis or transform into the decontrolled proliferation phenotype of cancer. Situated at a critical metabolic intersection, citrate, derived via glycolysis, serves as either a combustible fuel for aerobic mitochondrial bioenergetics or as a continuously replenished cytosolic carbon source for lipid biosynthesis, an essentially anaerobic process. Therein lies the paradox: under what conditions do cells control the metabolic route by which they process citrate? The Warburg effect exposes essentially the same dilemma—why do cancer cells, despite an abundance of oxygen needed for energy-generating mitochondrial respiration with citrate as fuel, avoid catabolizing mitochondrial citrate and instead rely upon accelerated glycolysis to support their energy requirements? This review details the genesis and consequences of the metabolic paradigm of a “truncated” Krebs/TCA cycle. Abundant data are presented for substrate utilization and membrane cholesterol enrichment in tumors that are consistent with criteria of the Warburg effect. From healthy cellular homeostasis to the uncontrolled proliferation of tumors, metabolic alterations center upon the loss of regulation of the cholesterol biosynthetic pathway. Deregulated tumor cholesterogenesis at the HMGR locus, generating enhanced carbon flux through the cholesterol synthesis pathway, is an absolute prerequisite for DNA synthesis and cell division. Therefore, expedited citrate efflux from cholesterol-enriched tumor mitochondria via the CTP/SLC25A1 citrate transporter is fundamental for sustaining the constant demand for cytosolic citrate that fuels the elevated flow of carbons from acetyl-CoA through the deregulated pathway of cholesterol biosynthesis.


2019 ◽  
Vol 5 (7) ◽  
pp. eaav3270 ◽  
Author(s):  
Diantha van de Vlekkert ◽  
Jeroen Demmers ◽  
Xinh-Xinh Nguyen ◽  
Yvan Campos ◽  
Eda Machado ◽  
...  

Lysosomal exocytosis is a ubiquitous process negatively regulated by neuraminidase 1 (NEU1), a sialidase mutated in the glycoprotein storage disease sialidosis. In Neu1−/− mice, excessive lysosomal exocytosis is at the basis of disease pathogenesis. Yet, the tissue-specific molecular consequences of this deregulated pathway are still unfolding. We now report that in muscle connective tissue, Neu1−/− fibroblasts have features of myofibroblasts and are proliferative, migratory, and exocytose large amounts of exosomes. These nanocarriers loaded with activated transforming growth factor–β and wingless-related integration site (WNT)/β-catenin signaling molecules propagate fibrotic signals to other cells, maintaining the tissue in a prolonged transitional status. Myofibroblast-derived exosomes fed to normal fibroblasts convert them into myofibroblasts, changing the recipient cells’ proliferative and migratory properties. These findings reveal an unexpected exosome-mediated signaling pathway downstream of NEU1 deficiency that propagates a fibrotic disease and could be implicated in idiopathic forms of fibrosis in humans.


2018 ◽  
Vol 19 (9) ◽  
pp. 2562 ◽  
Author(s):  
Maja Sabol ◽  
Diana Trnski ◽  
Vesna Musani ◽  
Petar Ozretić ◽  
Sonja Levanat

GLI transcription factors have important roles in intracellular signaling cascade, acting as the main mediators of the HH-GLI signaling pathway. This is one of the major developmental pathways, regulated both canonically and non-canonically. Deregulation of the pathway during development leads to a number of developmental malformations, depending on the deregulated pathway component. The HH-GLI pathway is mostly inactive in the adult organism but retains its function in stem cells. Aberrant activation in adult cells leads to carcinogenesis through overactivation of several tightly regulated cellular processes such as proliferation, angiogenesis, EMT. Targeting GLI transcription factors has recently become a major focus of potential therapeutic protocols.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3097-3097 ◽  
Author(s):  
Hendrik-Tobias Arkenau ◽  
Suzanne Fields Jones ◽  
Carla Kurkjian ◽  
Jeffrey R. Infante ◽  
Shubham Pant ◽  
...  

3097 Background: The PI3 kinase (PI3K) pathway is the most deregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is an oral highly specific and selective inhibitor of the PI3K and TORC1/2. The MTD (1200 mg) and toxicity profile of BEZ235 once daily dosing has been established. This study was designed to evaluate twice daily dosing of BEZ235 and its effect on treatment tolerability, PK, PD, and preliminary efficacy. Methods: Pts with advanced disease were enrolled in a 3+3 dose escalation schedule starting at 200 mg PO BID in 28 day cycles. For intrapatient PK comparison the first week pts received the total dose in a QD schedule. DLT assessment was in Cycle 1. Efficacy evaluations were every 2 cycles, and PK and PD were assessed. Results: 12 pts were enrolled at the following dose levels: 200 mg (n=3), 400 mg (n=3), 600 mg (n=3), and 600 mg (BID only, no QD lead-in) (n=3). No G4 AEs were reported. G3 related AEs were mucositis (n=2), AST/ALT elevation (n=2), anorexia (n=1) and diarrhea (n=1). The most common related G1/2 adverse events (AEs) were anorexia (n=6), diarrhea (n=3), fatigue (n=2), and headache (n=2). DLTs of G3 mucositis were observed in 2 patients at the 600 mg BID dose level with 1 week 1200 mg QD lead-in, which were attributed to the QD lead-in dosing during the first week. 3 pts then enrolled at 600 mg BID without lead in and had no further DLT. PK shows consistent increase in PK parameters with dose level. Of 10 evaluable, 3 pts had stable disease (13+ to 21+ weeks, 2 colorectal, 1 endometrial). Of 9 evaluable, 4 pts at various dose levels had decreased PET SUV uptake by greater than 25%. Conclusions: BEZ235 is tolerable at a dose of 600 mg BID, with less toxicity than has been seen with equivalent QD dosing. Preliminary signs of clinical and PD activity are noted.


2012 ◽  
Vol 34 (1) ◽  
pp. 22-25
Author(s):  
Rui Traquete ◽  
Heather M. Wallace

The vast majority of anticancer chemotherapeutic agents in clinical use have a high incidence of adverse side effects as a result of their lack of specificity towards malignant cells. The therapeutic use of these drugs is therefore limited, despite most of them having potent anti-tumour activity in vitro1. The non-specific actions can be overcome by targeting tumour cells more selectively than healthy cells and this is therefore a major challenge facing modern cancer therapy. Ideally, decreased uptake of these agents by healthy cells would not only decrease their associated toxicity, but also lower the dose required to kill the cancer cell. Current approaches to develop tumour-specific drugs are based on targeting a single deregulated pathway or an overexpressed receptor, and there are a number of molecules that successfully validate this strategy. These include monoclonal antibodies, peptides, folic acid, hormones and growth factors. Although demonstrating selective targeting is feasible, few of these agents are useful therapeutically, since most of the drugs have shown modest cell killing activity2. A valuable alternative to enhance drug specificity is to develop vector systems that have an enhanced affinity towards cancer cells. This would enable better use of already established chemotherapeutic agents as a result of preferential uptake and diminished secondary effects on healthy cells. Over the last few years, polyamine backbones have been studied as one such vector system, aiming to take advantage of the polyamine transport system (PTS) in cancer cells for selective delivery of known anticancer drugs. In this article, we describe the basic principles, as well as recent advances regarding this novel approach.


Sign in / Sign up

Export Citation Format

Share Document