Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate

Background Cell growth requires fatty acids for membrane synthesis. Fatty acids are assembled from 2-carbon units in the form of acetyl-CoA (AcCoA). In nutrient and oxygen replete conditions, acetyl-CoA is predominantly derived from glucose. In hypoxia, however, flux from glucose to acetyl-CoA decreases, and the fractional contribution of glutamine to acetyl-CoA increases. The significance of other acetyl-CoA sources, however, has not been rigorously evaluated. Here we investigate quantitatively, using 13C-tracers and mass spectrometry, the sources of acetyl-CoA in hypoxia.<p></p> Results In normoxic conditions, cultured cells produced more than 90% of acetyl-CoA from glucose and glutamine-derived carbon. In hypoxic cells, this contribution dropped, ranging across cell lines from 50% to 80%. Thus, under hypoxia, one or more additional substrates significantly contribute to acetyl-CoA production. 13C-tracer experiments revealed that neither amino acids nor fatty acids are the primary source of this acetyl-CoA. Instead, the main additional source is acetate. A large contribution from acetate occurs despite it being present in the medium at a low concentration (50–500 μM).<p></p> Conclusions Acetate is an important source of acetyl-CoA in hypoxia. Inhibition of acetate metabolism may impair tumor growth.<p></p&gt

Two-way Flow Networks with Small Decay

This paper characterizes the set of equilibrium networks in the two-way flow model of network formation with small decay, and this for all increasing benefit functions of the players. We show that as long as the population is large enough, this set contains large- as well as small-diameter networks. For all benefit functions, the periphery-sponsored star is the most stable. When the marginal benefits of information are constant, all non-star networks are equally stable. With increasing marginal benefits of information, small-diameter networks in general tend to be more stable. However, with decreasing marginal benefits of information, large-diameter networks tend to be the most robust along with the periphery-sponsored sta

Cancer metabolism at a glance

A defining hallmark of cancer is uncontrolled cell proliferation. This is initiated once cells have accumulated alterations in signaling pathways that control metabolism and proliferation, wherein the metabolic alterations provide the energetic and anabolic demands of enhanced cell proliferation. How these metabolic requirements are satisfied depends, in part, on the tumor microenvironment, which determines the availability of nutrients and oxygen. In this Cell Science at a Glance paper and the accompanying poster, we summarize our current understanding of cancer metabolism, emphasizing pathways of nutrient utilization and metabolism that either appear or have been proven essential for cancer cells. We also review how this knowledge has contributed to the development of anticancer therapies that target cancer metabolism

Evolutionary phase space in driven elliptical billiards

We perform the first long-time exploration of the classical dynamics of a driven billiard with a four dimensional phase space. With increasing velocity of the ensemble we observe an evolution from a large chaotic sea with stickiness due to regular islands to thin chaotic channels with diffusive motion leading to Fermi acceleration. As a surprising consequence, we encounter a crossover, which is not parameter induced but rather occurs dynamically, from amplitude dependent tunable subdiffusion to universal normal diffusion in momentum space. In the high velocity case we observe particle focusing in phase space.Comment: 5 pages, 4 figure

Sandpiles with height restrictions

We study stochastic sandpile models with a height restriction in one and two dimensions. A site can topple if it has a height of two, as in Manna's model, but, in contrast to previously studied sandpiles, here the height (or number of particles per site), cannot exceed two. This yields a considerable simplification over the unrestricted case, in which the number of states per site is unbounded. Two toppling rules are considered: in one, the particles are redistributed independently, while the other involves some cooperativity. We study the fixed-energy system (no input or loss of particles) using cluster approximations and extensive simulations, and find that it exhibits a continuous phase transition to an absorbing state at a critical value zeta_c of the particle density. The critical exponents agree with those of the unrestricted Manna sandpile.Comment: 10 pages, 14 figure

Activated Random Walkers: Facts, Conjectures and Challenges

We study a particle system with hopping (random walk) dynamics on the integer lattice $\mathbb Z^d$. The particles can exist in two states, active or inactive (sleeping); only the former can hop. The dynamics conserves the number of particles; there is no limit on the number of particles at a given site. Isolated active particles fall asleep at rate $\lambda > 0$, and then remain asleep until joined by another particle at the same site. The state in which all particles are inactive is absorbing. Whether activity continues at long times depends on the relation between the particle density $\zeta$ and the sleeping rate $\lambda$. We discuss the general case, and then, for the one-dimensional totally asymmetric case, study the phase transition between an active phase (for sufficiently large particle densities and/or small $\lambda$) and an absorbing one. We also present arguments regarding the asymptotic mean hopping velocity in the active phase, the rate of fixation in the absorbing phase, and survival of the infinite system at criticality. Using mean-field theory and Monte Carlo simulation, we locate the phase boundary. The phase transition appears to be continuous in both the symmetric and asymmetric versions of the process, but the critical behavior is very different. The former case is characterized by simple integer or rational values for critical exponents ($\beta = 1$, for example), and the phase diagram is in accord with the prediction of mean-field theory. We present evidence that the symmetric version belongs to the universality class of conserved stochastic sandpiles, also known as conserved directed percolation. Simulations also reveal an interesting transient phenomenon of damped oscillations in the activity density

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism