Subverting sterols: rerouting an oxysterol-signaling pathway to promote tumor growth.

Oxysterols are oxidized derivatives of cholesterol that are generated enzymatically or through autoxidation. Initially identified as important lipid signaling molecules in the context of atherosclerosis and inflammation, accumulated evidence indicates that these lipid-signaling molecules can have pleiotropic effects on the fate and function of the immune system. These effects range from the regulation of immune cell survival and proliferation to chemotaxis and antiviral immunity. New studies now indicate that tumor-derived oxysterols can serve to subvert the immune system by recruiting protumorigenic neutrophils into the tumor microenvironment. The consequence of this recruitment is the generation of proangiogenic factors and matrix metalloproteinase proteins that provide a tumor a significant growth and survival advantage. In combination with other recent studies, these data highlight the ongoing cross talk between sterol metabolism and the immune system, and they raise the intriguing possibility that targeting oxysterol pathways could serve as a novel therapeutic approach in the war on cancer

Doxycycline alters metabolism and proliferation of human cell lines.

The tetracycline antibiotics are widely used in biomedical research as mediators of inducible gene expression systems. Despite many known effects of tetracyclines on mammalian cells-including inhibition of the mitochondrial ribosome-there have been few reports on potential off-target effects at concentrations commonly used in inducible systems. Here, we report that in human cell lines, commonly used concentrations of doxycycline change gene expression patterns and concomitantly shift metabolism towards a more glycolytic phenotype, evidenced by increased lactate secretion and reduced oxygen consumption. We also show that these concentrations are sufficient to slow proliferation. These findings suggest that researchers using doxycycline in inducible expression systems should design appropriate controls to account for potential confounding effects of the drug on cellular metabolism

Phenotype of Transgenic Mice Carrying a Very Low Copy Number of the Mutant Human G93A Superoxide Dismutase-1 Gene Associated with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor neuron. While most cases of ALS are sporadic, 10% are familial (FALS) with 20% of FALS caused by a mutation in the gene that codes for the enzyme Cu/Zn superoxide dismutase (SOD1). There is variability in sporadic ALS as well as FALS where even within the same family some siblings with the same mutation do not manifest disease. A transgenic (Tg) mouse model of FALS containing 25 copies of the mutant human SOD1 gene demonstrates motor neuron pathology and progressive weakness similar to ALS patients, leading to death at approximately 130 days. The onset of symptoms and survival of these transgenic mice are directly related to the number of copies of the mutant gene. We report the phenotype of a very low expressing (VLE) G93A SOD1 Tg carrying only 4 copies of the mutant G93ASOD1 gene. While weakness can start at 9 months, only 74% of mice 18 months or older demonstrate disease. The VLE mice show decreased motor neurons compared to wild-type mice as well as increased cytoplasmic translocation of TDP-43. In contrast to the standard G93A SOD1 Tg mouse which always develops motor weakness leading to death, not all VLE animals manifested clinical disease or shortened life span. In fact, approximately 20% of mice older than 24 months had no motor symptoms and only 18% of VLE mice older than 22 months reached end stage. Given the variable penetrance of clinical phenotype, prolonged survival, and protracted loss of motor neurons the VLE mouse provides a new tool that closely mimics human ALS. This tool will allow the study of pathologic events over time as well as the study of genetic and environmental modifiers that may not be causative, but can exacerbate or accelerate motor neuron disease

Subverting sterols: rerouting an oxysterol-signaling pathway to promote tumor growth

Oxysterols are oxidized derivatives of cholesterol that are generated enzymatically or through autoxidation. Initially identified as important lipid signaling molecules in the context of atherosclerosis and inflammation, accumulated evidence indicates that these lipid-signaling molecules can have pleiotropic effects on the fate and function of the immune system. These effects range from the regulation of immune cell survival and proliferation to chemotaxis and antiviral immunity. New studies now indicate that tumor-derived oxysterols can serve to subvert the immune system by recruiting protumorigenic neutrophils into the tumor microenvironment. The consequence of this recruitment is the generation of proangiogenic factors and matrix metalloproteinase proteins that provide a tumor a significant growth and survival advantage. In combination with other recent studies, these data highlight the ongoing cross talk between sterol metabolism and the immune system, and they raise the intriguing possibility that targeting oxysterol pathways could serve as a novel therapeutic approach in the war on cancer

Federal Reserve Bank of New York Meeting with AIG Notes

In this particular instance, AIG faced liquidity issues that threatened the company\u27s survival

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies