Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells.

Serine and glycine give rise to important building blocks in proliferating cells. Both amino acids are either synthesized de novo or taken up from the extracellular space. In lung cancer, serine synthesis gene expression is variable, yet, expression of the initial enzyme, phosphoglycerate dehydrogenase (PHGDH), was found to be associated with poor prognosis. While the contribution of de novo synthesis to serine pools has been shown to be enhanced by serine starvation, the impact of glucose deprivation, a commonly found condition in solid cancers is poorly understood. Here, we utilized a stable isotopic tracing approach to assess serine and glycine de novo synthesis and uptake in different lung cancer cell lines and normal bronchial epithelial cells in variable serine, glycine, and glucose conditions. Under low glucose supplementation (0.2 mM, 3-5% of normal plasma levels), serine de novo synthesis was maintained or even activated. As previously reported, also gluconeogenesis supplied carbons from glutamine to serine and glycine under these conditions. Unexpectedly, low glucose treatment consistently enhanced serine to glycine conversion, along with an up-regulation of the mitochondrial one-carbon metabolism enzymes, serine hydroxymethyltransferase (SHMT2) and methylenetetrahydrofolate dehydrogenase (MTHFD2). The relative contribution of de novo synthesis greatly increased in low serine/glycine conditions. In bronchial epithelial cells, adaptations occurred in a similar fashion as in cancer cells, but serine synthesis and serine to glycine conversion, as assessed by label enrichments and gene expression levels, were generally lower than in (PHGDH positive) cancer cells. In summary, we found a variable contribution of glucose or non-glucose carbon sources to serine and glycine and a high adaptability of the downstream one-carbon metabolism pathway to variable glucose supply.

Flexibility and Adaptation of Cancer Cells in a Heterogenous Metabolic Microenvironment.

The metabolic microenvironment, comprising all soluble and insoluble nutrients and co-factors in the extracellular milieu, has a major impact on cancer cell proliferation and survival. A large body of evidence from recent studies suggests that tumor cells show a high degree of metabolic flexibility and adapt to variations in nutrient availability. Insufficient vascular networks and an imbalance of supply and demand shape the metabolic tumor microenvironment, which typically contains a lower concentration of glucose compared to normal tissues. The present review sheds light on the recent literature on adaptive responses in cancer cells to nutrient deprivation. It focuses on the utilization of alternative nutrients in anabolic metabolic pathways in cancer cells, including soluble metabolites and macromolecules and outlines the role of central metabolic enzymes conferring metabolic flexibility, like gluconeogenesis enzymes. Moreover, a conceptual framework for potential therapies targeting metabolically flexible cancer cells is presented.

Biosensor platforms for rapid HIV detection.

Human immunodeficiency virus (HIV), a type of lentivirus (a subgroup of retrovirus), causes acquired immunodeficiency syndrome (AIDS). This pathophysiologic state destroys the immune system allowing opportunistic infections, cancer and other life-threatening diseases to thrive. Although many analytic tools including enzyme-linked immunoassay (ELISA), indirect and line immunoassay, Western blotting, radio-immunoprecipitation, nucleic acid amplification testing (NAAT) have been developed to detect HIV, recent developments in nanosensor technology have prompted its use as a novel diagnostic approach. Nanosensors provide analytical information about behavior and characteristics of particles by using biochemical reactions mediated by enzymes, immune components, cells and tissues. These reactions are transformed into decipherable signals, i.e., electrical, thermal, optical, using nano to micro scale technology. Nanosensors are capable of both quantitative and qualitative detection of HIV, are highly specific and sensitive and provide rapid reproducible results. Nanosensor technology can trace infant infection during mother-to-child transmission, the latent HIV pool and monitor anti-HIV therapy. In this chapter, we review nanosensor analytics including electrochemical, optical, piezoelectric, SERS-based lateral flow assay, microfluidic channel-based biosensors in the detection of HIV. Other techniques in combination with different biorecognition elements (aptamers, antibodies, oligonucleotides) are also discussed.