ATP-Citrate Lyase: A Key Player in Cancer Metabolism

ATP-citrate lyase (ACLY) is a cytosolic enzyme that catalyzes the generation of acetyl CoA from citrate. Acetyl CoA is a vital building block for the endogenous biosynthesis of fatty acids and cholesterol and is involved in isoprenoid-based protein modifications. Acetyl CoA is also required for acetylation reactions that modify proteins, such as histone acetylation. ACLY is upregulated or activated in several types of cancers, and its inhibition is known to induce proliferation arrest in cancer cells both in vitro and in vivo. The present review highlights current knowledge about the role of ACLY in cancer cells, with special reference to the different pathways that are linked by ACLY. Cancer Res; 72(15); 3709-14. ?2012 AACR.     

Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons

Spiral ganglion neurons often degenerate in the deaf ear, compromising the function of cochlear implants. Cochlear implant function can be improved by good preservation of the spiral ganglion neurons, which are the target of electrical stimulation by the implant. Brain derived neurotrophic factor (BDNF) has previously been shown to enhance spiral ganglion survival in experimentally deafened ears. Providing enhanced levels of BDNF in human ears may be accomplished by one of several different methods. The goal of these experiments was to test a modified design of the cochlear implant electrode that includes a coating of fibroblast cells transduced by a viral vector with a BDNF gene insert. To accomplish this type of ex vivo gene transfer, we transduced guinea pig fibroblasts with an adenovirus with a BDNF gene cassette insert, and determined that these cells secreted BDNF. We then attached BDNF-secreting cells to the cochlear implant electrode via an agarose gel, and implanted the electrode in the scala tympani. We determined that the BDNF expressing electrodes were able to preserve significantly more spiral ganglion neurons in the basal turns of the cochlea after 48 days of implantation when compared to control electrodes. This protective effect decreased in the higher cochlear turns. The data demonstrate the feasibility of combining cochlear implant therapy with ex vivo gene transfer for enhancing spiral ganglion neuron survival.     

De novo lipogenesis in health and disease

Background

De novo lipogenesis (DNL) is a complex and highly regulated metabolic pathway. In normal conditions DNL converts excess carbohydrate into fatty acids that are then esterified to storage triacylglycerols (TGs). These TGs could later provide energy via β-oxidation. In human body this pathway is primarily active in liver and adipose tissue. However, it is considered to be a minor contributor to the serum lipid homeostasis. Deregulations in the lipogenic pathway are associated with diverse pathological conditions.

Scope of review

The present review focuses on our current understanding of the lipogenic pathway with special reference to the causes and consequences of aberrant DNL.

Major conclusions

The deregulation of DNL in the major lipogenic tissues of the human body is often observed in various metabolic anomalies — including obesity, non-alcoholic fatty liver disease and metabolic syndrome. In addition to that de novo lipogenesis is reported to be exacerbated in cancer tissues, virus infected cells etc. These observations suggest that inhibitors of the DNL pathway might serve as therapeutically significant compounds. The effectiveness of these inhibitors in treatment of cancer and obesity has been suggested by previous works.

General significance

De novo lipogenesis – which is an intricate and highly regulated pathway – can lead to adverse metabolic consequences when deregulated. Therapeutic targeting of this pathway may open a new window of opportunity for combating various lipogenesis-driven pathological conditions — including obesity, cancer and certain viral infections.     

ATP Citrate Lyase Knockdown Induces Growth Arrest and Apoptosis through Different Cell- and Environment-Dependent Mechanisms

ATP citrate lyase (ACLY) is a cytosolic enzyme that catalyzes generation of acetyl-CoA, which is a vital building block for fatty acid, cholesterol, and isoprenoid biosynthesis. ACLY is upregulated in several types of cancer, and its inhibition induces proliferation arrest in certain cancer cells. As ACLY is involved in several pathways, its downregulation may affect multiple processes. Here, we have shown that short hairpin RNA-mediated ACLY silencing in cell lines derived from different types of cancers induces proliferation, cell-cycle arrest, and apoptosis. However, this antiproliferative effect of ACLY knockdown was observed only when cells were cultivated under lipid-reduced growth conditions. Proliferation arrest induced by ACLY silencing was partially rescued by supplementing the media with fatty acids and/or cholesterol. This indicates that the ACLY knockdown-mediated growth arrest might be the result of either fatty acid or cholesterol starvation or both. In the absence of ACLY, the cancer cells displayed elevated expression of sterol regulatory element binding protein-regulated downstream genes involved in de novo fatty acid and cholesterol biosynthesis. Furthermore, ACLY suppression resulted in elevated expression of acyl-CoA synthetase short-chain family member 2 (ACSS2), an enzyme that also produces acetyl-CoA using acetate as a substrate. Acetate supplementation partially rescued the cancer cells from ACLY suppression-induced proliferation arrest. We also observed that the absence of ACLY enhanced ACSS2-dependent lipid synthesis. These findings provide new insights into the role of ACLY in cancer cell growth and give critical information about the effects of ACLY silencing on different pathways. This information is crucial in understanding the possible application of ACLY inhibition in cancer therapeutics. Mol Cancer Ther; 11(9); 1925-35. ?2012 AACR.     

Investigation of piperidine derivatives in ex vivo models of pain and platelet aggregation

Piperidine derivatives are known to exhibit analgesic activities and are likely to possess the ability to block the effects of prostaglandins through inhibition of downstream signaling pathways. The present study investigated the activity of five derivatives (PD2-6) of 4-(4??-bromophenyl)-4-piperidinol (PD1), against pain and platelet aggregation mediated by the release of prostaglandins and thromboxane A2, respectively. The results showed that compound PD1 and its two phenacyl derivatives PD3 and PD5 exhibited a highly significant analgesic effect (p < 0.01), whereas PD4 and PD6 also showed significant activity. PD3, the most active analgesic compound when docked to the opioid receptor, had interactions between the oxygen of its nitro group and the amino group of ARG 573, indicating a distance of 1.2563 ?. The antiplatelet data showed that compound PD5 (4-(4??-bromo-phenyl)-4-hydroxy-1-[2-(2??,4??-dimethoxyphenyl)-2-oxo-ethyl]-piperidinium bromide) had an IC₅₀ = 0.06 mM, which was the most active compound, whereas PD3 was the second most active compound against platelet aggregating factor-induced aggregation with an IC₅₀ = 80 mM. Acetyl salicylic acid (IC₅₀ = 150 ??M) was used as a positive control.     

Expression of lipid transport-associated genes in lipid-deprived cancer cells

Cancer cells are known to significantly alter their lipid profiles in response to changes in extracellular lipid availability. Recent studies have shown that in response to lipid deprivation, cancer cells display significant changes in their cellular lipid homeostasis. These changes have been linked to the modulation of de novo lipid synthesis pathways that are markedly altered under lipid-deprived growth conditions. However, the effects of such environment on intracellular lipid trafficking—that could also affect cellular lipid homeostasis—have not been widely investigated. The presented work studies the effect of lipid deprivation on expression of genes for lipid transport proteins (LTPs) in cancer cell lines.     

Identification of unique binding site and molecular docking studies for structurally diverse Bcl-xL inhibitors

B-cell lymphoma extra large (Bcl-xL) is a member of the Bcl-2 family of proteins. This family has been implicated in the survival of cancer cells. Bcl-xL is known to be over-expressed in hematopoietic disorders and various types of cancers. The purpose of the present study is to develop an in silico model allowing for the identification of structural features influencing the inhibitory activity of Bcl-xL protein based on a diverse dataset of 104 compounds. Molecular docking studies are carried out to explore the binding of structurally diverse inhibitors to Bcl-xL by AutoDock and GOLD programs. The outcome of this investigation establishes the molecular basis for inhibition of Bcl-xL. Most of the compounds docked into the active site of Bcl-xL (PDB code 1R2D) with good docking scores and binding mode. The docking analysis of the highest active molecules—compound 50 (AutoDock binding affinity ?10.8) and compound 100 (GoldScore 53.0)—from both the docking programs showed significant interaction with active site amino acid residues and H-bond interactions with the key amino acid residues. Current study identified a novel binding site of Bcl-xL protein. Forty compounds bound to this new binding site which is different from the formerly characterized hydrophobic pocket. The energy values of these potent compounds are also comparable with those binding to the previously reported binding site. This finding will help the researchers in the design of a better drug for the treatment of cancers.     

Rising Metals Concentration in the Environment: A Response to Effluents of Leather Industries in Sialkot

Bulletin of Environmental Contamination and Toxicology - Many leather processing industries in Sialkot, Pakistan, discharge their wastes freely into the environment which then enters nearby water...