Glucose Exhaustion Research Articles

The familial amyotrophic lateral sclerosis-associated A4V SOD1 mutant is not able to regulate aerobic glycolysis

Under certain stress conditions, astrocytes operate in aerobic glycolysis, a process controlled by pyruvate dehydrogenase (PDH) inhibition through its E1 α subunit (Pda1) phosphorylation. This supplies lactate to neurons, which save glucose to obtain NADPH to, among other roles, counteract reactive oxygen species. A failure in this metabolic cooperation causes severe damage to neurons. In this work, using humanized Saccharomyces cerevisiae cells in which its endogenous Cu/Zn Superoxide Dismutase (SOD1) was replaced by human ortholog, we investigated the role of human SOD1 (hSOD1) in aerobic glycolysis regulation and its implications to amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. Yeast cells ferment glucose even in the presence of oxygen and switch to respiratory metabolism after glucose exhaustion. However, like cells of SOD1-knockout strain, cells expressing A4V mutant of hSOD1 growing on glucose showed a respiratory phenotype, i.e., low glucose and high oxygen consumptions and low intracellular oxidation levels in response to peroxide stress, contrary to cells expressing wild-type (WT) SOD1 (yeast or human). The A4V mutation in hSOD1 is linked to ALS. In contrast to WT SOD1 strains, PDH activity of both sod1Δ and A4V hSOD1 cells did not change in response to a metabolic shift toward oxidative metabolism, which was associated to lower Pda1 phosphorylation levels under growth on glucose. Taken together, our results suggest that A4V mutant cannot regulate aerobic glycolysis via Pda1 phosphorylation the same way WT hSOD1, which might be linked to problems observed in the motor neurons of ALS patients with the SOD1 A4V mutation.

A fast method to distinguish between fermentative and respiratory metabolisms in single yeast cells

Saccharomyces cerevisiae adjusts its metabolism based on nutrient availability, typically transitioning from glucose fermentation to ethanol respiration as glucose becomes limiting. However, our understanding of the regulation of metabolism is largely based on population averages, whereas nutrient transitions may cause heterogeneous responses. Here we introduce iCRAFT, a method that couples the ATP Förster resonance energy transfer (FRET)-based biosensor yAT1.03 with Antimycin A to differentiate fermentative and respiratory metabolisms in individual yeast cells. Upon Antimycin A addition, respiratory cells experienced a sharp decrease of the normalized FRET ratio, while respiro-fermentative cells showed no response. Next, we tracked changes in metabolism during the diauxic shift of a glucose pre-grown culture. Following glucose exhaustion, the entire cell population experienced a progressive rise in cytosolic ATP produced via respiration, suggesting a gradual increase in respiratory capacity. Overall, iCRAFT is a robust tool to distinguish fermentation from respiration, offering a new single-cell opportunity to study yeast metabolism.

Low-temperature photothermal-induced alkyl radical release facilitates dihydroartemisinin-triggered “valve-off” starvation therapy

The high nutrient and energy demand of tumor cells compared to normal cells to sustain rapid proliferation offer a potentially auspicious avenue for implementing starvation therapy. However, conventional starvation therapy, such as glucose exhaustion and vascular thrombosis, can lead to systemic toxicity and exacerbate tumor hypoxia. Herein, we developed a new “valve-off” starvation tactic, which was accomplished by closing the valve of glucose transporter protein 1 (GLUT1). Specifically, dihydroartemisinin (DHA), 2,20-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AI), and Ink were co-encapsulated in a sodium alginate (ALG) hydrogel. Upon irradiation with the 1064 nm laser, AI rapidly disintegrated into alkyl radicals (R•), which exacerbated the DHA-induced mitochondrial damage through the generation of reactive oxygen species and further reduced the synthesis of adenosine triphosphate (ATP). Simultaneously, the production of R• facilitated DHA-induced starvation therapy by suppressing GLUT1, which in turn reduced glucose uptake. Systematic in vivo and in vitro results suggested that this radical-enhanced “valve-off” strategy for inducing tumor cell starvation was effective in reducing glucose uptake and ATP levels. This integrated strategy induces tumor starvation with efficient tumor suppression, creating a new avenue for controlled, precise, and concerted tumor therapy.

Modulated Arabinose Uptake and cAMP Signaling Synergistically Improve Glucose and Arabinose Consumption in Recombinant Yeast.

During the production of ethanol from lignocellulose-derived sugars, recombinant yeasts tend to utilize xylose and arabinose after glucose exhaustion. So far, many glucose-insensitive pentose transporters have been reported to counteract this phenomenon, but few studies have described intracellular factors. In this study, the combination of adaptive evolution, comparative genomics, and genetic complementation revealed that the hexokinase-deficient (Hxk0) arabinose-fermenting Saccharomyces cerevisiae requires the arabinose transporter variant Gal2-N376T and the mutations of guanine nucleotide exchange factor Cdc25 to overcome glucose restriction during arabinose assimilation. The results showed that the Hxk0 recombinant yeasts could lower the metabolic/physiological threshold of cell proliferation by downregulating the intracellular cAMP levels, resulting in smaller cells and increased arabinose assimilation under glucose restriction. In the medium containing 80 g/L glucose and 20 g/L arabinose, the evolved strain restoring the hexokinase activity completed fermentation at 22 h, compared to 24 h for the parental strain. Overall, the experimental results provide new insights into glucose repression of biorefinery yeasts.

Proteome Dynamics During Transition From Exponential to Stationary Phase Under Aerobic and Anaerobic Conditions in Yeast

The yeast Saccharomyces cerevisiae is a widely-used eukaryotic model organism and a promising cell factory for industry. However, despite decades of research, the regulation of its metabolism is not yet fully understood, and its complexity represents a major challenge for engineering and optimizing biosynthetic routes. Recent studies have demonstrated the potential of resource and proteomic allocation data in enhancing models for metabolic processes. However, comprehensive and accurate proteome dynamics data that can be used for such approaches are still very limited. Therefore, we performed a quantitative proteome dynamics study to comprehensively cover the transition from exponential to stationary phase for both aerobically and anaerobically grown yeast cells. The combination of highly controlled reactor experiments, biological replicates, and standardized sample preparation procedures ensured reproducibility and accuracy. In addition, we selected the CEN.PK lineage for our experiments because of its relevance for both fundamental and applied research. Together with the prototrophic standard haploid strain CEN.PK113-7D, we also investigated an engineered strain with genetic minimization of the glycolytic pathway, resulting in the quantitative assessment of 54 proteomes. The anaerobic cultures showed remarkably less proteome-level changes compared with the aerobic cultures, during transition from the exponential to the stationary phase as a consequence of the lack of the diauxic shift in the absence of oxygen. These results support the notion that anaerobically growing cells lack resources to adequately adapt to starvation. This proteome dynamics study constitutes an important step toward better understanding of the impact of glucose exhaustion and oxygen on the complex proteome allocation process in yeast. Finally, the established proteome dynamics data provide a valuable resource for the development of resource allocation models as well as for metabolic engineering efforts.

In situ microwave fixation provides an instantaneous snapshot of the brain metabolome

Brain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. In particular, we demonstrate exhaustion of glycogen and glucose and an increase in lactate production during conventional rapid brain resection and preservation by liquid nitrogen. In contrast, we show that these postmortem changes are not observed with simultaneous animal sacrifice and in situ fixation with focused, high-power microwave. We further employ microwave fixation to define brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple brain regions, evidenced by reduced 13C enrichment into glycogen, glycolysis, and the tricarboxylic acid (TCA) cycle. Reduced glucose metabolism correlated with a marked decrease in GLUT2 expression and several metabolic enzymes in unique brain regions. In conclusion, our study supports the incorporation of microwave fixation for more accurate studies of brain metabolism in rodent models.

Serine metabolism contributes to cell survival by regulating extracellular pH and providing an energy source in Saccharomyces cerevisiae.

Changes in extracellular pH affect the homeostasis and survival of unicellular organisms. Supplementation of culture media with amino acids can extend the lifespan of budding yeast, Saccharomyces cerevisiae, by alleviating the decrease in pH. However, the optimal amino acids to use to achieve this end, and the underlying mechanisms involved, remain unclear. Here, we describe the specific role of serine metabolism in the regulation of pH in a medium. The addition of serine to synthetic minimal medium suppressed acidification, and at higher doses increased the pH. CHA1, which encodes a catabolic serine hydratase that degrades serine into ammonium and pyruvate, is essential for serine-mediated alleviation of acidification. Moreover, serine metabolism supports extra growth after glucose depletion. Therefore, medium supplementation with serine can play a prominent role in the batch culture of budding yeast, controlling extracellular pH through catabolism into ammonium and acting as an energy source after glucose exhaustion.

BY4741 cannot enter quiescence from rich medium.

In rich medium, W303 Saccharomyces cerevisiae begins to accumulate in G1 an hour before it exhausts the available glucose. It undergoes one more asymmetrical cell division, then stops dividing in G1. In contrast, BY4741, stops dividing four hours before glucose exhaustion, at one-fourth the cell density achieved by W303. There is no asymmetrical cell division and only 50% of the cells arrest in G1. We conclude that BY4741 growth is not limited by glucose and they do not go through the stereotypical events carried out by other strains as they enter quiescence from rich medium. In W303, the timing of glucose limitation and the transition to quiescence is correlated with the rate of biomass accumulation and cell doubling time.

Mineral medium design based on macro and trace element requirements for high cell density cultures of Priestia megaterium DSM 509

To assess the suitability of a mineral medium selected from the literature for high cell density cultivations of Priestia megaterium DSM 509 (ultimately for producing PHA), fermentations were planned and tested in a (2 L) bioreactor. After few hours of a batch culture, growth was limited despite an efficient oxygenation and the relative abundance of macronutrients, suggesting trace elements (TE) deficiencies. They had to be increased to achieve higher growth rates and cell densities. Growth was improved by adding up to 10 times more TE as maximum growth rate increased from 0.20 to 2.36 g L−1 h−1, but eventually growth limitations occurred. Major and trace minerals were therefore determined by ICP-OES. These analyses showed that the selected medium was deficient mainly in Co, Mn and Zn. Requirements for 11 minerals could then be assessed and used to formulate a new mineral medium. Tested in a fed-batch culture assigned to a specific growth rate of 0.2 h−1, it allowed P. megaterium to grow in 8 h during the batch phase without being limited until the exhaustion of glucose. In the fed-batch phase, high cell densities of 53.6 g L−1 were reached after 10 h with a space-time yield of 2.96 g L−1 h−1.

A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes.

Existing immune signatures and tumor mutational burden have only modest predictive capacity for the efficacy of immune check point inhibitors. In this study, we developed an immune-metabolic signature suitable for personalized ICI therapies. A classifier using an immune-metabolic signature (IMMETCOLS) was developed on a training set of 77 metastatic colorectal cancer (mCRC) samples and validated on 4,200 tumors from the TCGA database belonging to 11 types. Here, we reveal that the IMMETCOLS signature classifies tumors into three distinct immune-metabolic clusters. Cluster 1 displays markers of enhanced glycolisis, hexosamine byosinthesis and epithelial-to-mesenchymal transition. On multivariate analysis, cluster 1 tumors were enriched in pro-immune signature but not in immunophenoscore and were associated with the poorest median survival. Its predicted tumor metabolic features suggest an acidic-lactate-rich tumor microenvironment (TME) geared to an immunosuppressive setting, enriched in fibroblasts. Cluster 2 displays features of gluconeogenesis ability, which is needed for glucose-independent survival and preferential use of alternative carbon sources, including glutamine and lipid uptake/β-oxidation. Its metabolic features suggest a hypoxic and hypoglycemic TME, associated with poor tumor-associated antigen presentation. Finally, cluster 3 is highly glycolytic but also has a solid mitochondrial function, with concomitant upregulation of glutamine and essential amino acid transporters and the pentose phosphate pathway leading to glucose exhaustion in the TME and immunosuppression. Together, these findings suggest that the IMMETCOLS signature provides a classifier of tumors from diverse origins, yielding three clusters with distinct immune-metabolic profiles, representing a new predictive tool for patient selection for specific immune-metabolic therapeutic approaches.

Using fluorescent promoter-reporters to study sugar utilization control in Bifidobacterium longum NCC 2705

Bifidobacteria are amongst the first bacteria to colonize the human gastro-intestinal system and have been proposed to play a crucial role in the development of the infant gut since their absence is correlated to the development of diseases later in life. Bifidobacteria have the capacity to metabolize a diverse range of (complex) carbohydrates, reflecting their adaptation to the lower gastro-intestinal tract. Detailed understanding of carbohydrate metabolism regulation in this genus is of prime importance and availability of additional genetic tools easing such studies would be beneficial. To develop a fluorescent protein-based reporter system that can be used in B. longum NCC 2705, we first selected the most promising fluorescent protein out of the seven we tested (i.e., mCherry). This reporter protein was then used to study the carbohydrate mediated activation of PBl1518 and PBl1694, two promoters respectively predicted to be controlled by the transcriptional factors AraQ and AraU, previously suggested to regulate arabinose utilization and proposed to also act as global transcriptional regulators in bifidobacteria. We confirmed that in B. longum NCC 2705 the AraQ controlled promoter (PBl1518) is induced strongly by arabinose and established that the AraU controlled promoter (PBl1694) was mostly induced by the hexoses galactose and fructose. Combining the mCherry reporter system with flow cytometry, we established that NCC 2705 is able to co-metabolize arabinose and glucose while galactose was only consumed after glucose exhaustion, thus illustrating the complexity of different carbohydrate consumption patterns and their specific regulation in this strain.

Sterol Metabolism Differentially Contributes to Maintenance and Exit of Quiescence.

Nutrient starvation initiates cell cycle exit and entry into quiescence, a reversible, non-proliferative state characterized by stress tolerance, longevity and large-scale remodeling of subcellular structures. Depending on the nature of the depleted nutrient, yeast cells are assumed to enter heterogeneous quiescent states with unique but mostly unexplored characteristics. Here, we show that storage and consumption of neutral lipids in lipid droplets (LDs) differentially impacts the regulation of quiescence driven by glucose or phosphate starvation. Upon prolonged glucose exhaustion, LDs were degraded in the vacuole via Atg1-dependent lipophagy. In contrast, yeast cells entering quiescence due to phosphate exhaustion massively over-accumulated LDs that clustered at the vacuolar surface but were not engulfed via lipophagy. Excessive LD biogenesis required contact formation between the endoplasmic reticulum and the vacuole at nucleus-vacuole junctions and was accompanied by a shift of the cellular lipid profile from membrane towards storage lipids, driven by a transcriptional upregulation of enzymes generating neutral lipids, in particular sterol esters. Importantly, sterol ester biogenesis was critical for long-term survival of phosphate-exhausted cells and supported rapid quiescence exit upon nutrient replenishment, but was dispensable for survival and regrowth of glucose-exhausted cells. Instead, these cells relied on de novo synthesis of sterols and fatty acids for quiescence exit and regrowth. Phosphate-exhausted cells efficiently mobilized storage lipids to support several rounds of cell division even in presence of inhibitors of fatty acid and sterol biosynthesis. In sum, our results show that neutral lipid biosynthesis and mobilization to support quiescence maintenance and exit is tailored to the respective nutrient scarcity.

Phosphate Restriction Promotes Longevity via Activation of Autophagy and the Multivesicular Body Pathway.

Nutrient limitation results in an activation of autophagy in organisms ranging from yeast, nematodes and flies to mammals. Several evolutionary conserved nutrient-sensing kinases are critical for efficient adaptation of yeast cells to glucose, nitrogen or phosphate depletion, subsequent cell-cycle exit and the regulation of autophagy. Here, we demonstrate that phosphate restriction results in a prominent extension of yeast lifespan that requires the coordinated activity of autophagy and the multivesicular body pathway, enabling efficient turnover of cytoplasmic and plasma membrane cargo. While the multivesicular body pathway was essential during the early days of aging, autophagy contributed to long-term survival at later days. The cyclin-dependent kinase Pho85 was critical for phosphate restriction-induced autophagy and full lifespan extension. In contrast, when cell-cycle exit was triggered by exhaustion of glucose instead of phosphate, Pho85 and its cyclin, Pho80, functioned as negative regulators of autophagy and lifespan. The storage of phosphate in form of polyphosphate was completely dispensable to in sustaining viability under phosphate restriction. Collectively, our results identify the multifunctional, nutrient-sensing kinase Pho85 as critical modulator of longevity that differentially coordinates the autophagic response to distinct kinds of starvation.

Regulation of ytfK by cAMP-CRP Contributes to SpoT-Dependent Accumulation of (p)ppGpp in Response to Carbon Starvation YtfK Responds to Glucose Exhaustion.

Guanosine penta- or tetraphosphate (known as (p)ppGpp) serves as second messenger to respond to nutrient downshift and other environmental stresses, a phenomenon called stringent response. Accumulation of (p)ppGpp promotes the coordinated inhibition of macromolecule synthesis, as well as the activation of stress response pathways to cope and adapt to harmful conditions. In Escherichia coli, the (p)ppGpp level is tightly regulated by two enzymes, the (p)ppGpp synthetase RelA and the bifunctional synthetase/hydrolase SpoT. We recently identified the small protein YtfK as a key regulator of SpoT-mediated activation of stringent response in E. coli. Here, we further characterized the regulation of ytfK. We observed that ytfK is subjected to catabolite repression and is positively regulated by the cyclic AMP (cAMP)-cAMP receptor protein (CRP) complex. Importantly, YtfK contributes to SpoT-dependent accumulation of (p)ppGpp and cell survival in response to glucose starvation. Therefore, regulation of ytfK by the cAMP-CRP appears important to adjust (p)ppGpp level and coordinate cellular metabolism in response to glucose availability.

Communication—An Epidermal Electrochemical Energy Source with a Replaceable Glucose Power Supply Membrane

This paper presents an epidermal electrochemical energy source with a replaceable glucose membrane to continuously energize wearable sensors. In the anode, glucose oxidase catalytically decomposes glucose molecules, producing electrons, while in the cathode, with the achieved electrons, laccase catalytically decomposes oxygen, making electricity. Most significantly, the glucose membrane on the anode can be repeatedly replaced when the electrical energy is depleted due to the exhaustion of glucose, making long term power supply possible. Experimental results indicate that the energy source can provide a stable output of ∼0.015 mW cm−2 electrical power with an open-circuit voltage of ∼240 mV.

The production of bacterial cellulose in Gluconacetobacter xylinus regulated by luxR overexpression of quorum sensing system.

Quorum sensing is a mechanism that facilitates cell-to-cell communication. Through signal molecular density for signal recognition, which leads to the regulation of some physiological and biochemical functions. Gluconacetobacter xylinus CGMCC 2955, which produces bacterial cellulose (BC), synthesizes the LuxR protein belonging to the LuxI/LuxR type QS system. Here, a luxR overexpression vector was transformed into G. xylinus CGMCC 2955. The overexpression of luxR increased the yield of BC by 15.6% after 16days static culture and reduced the cell density by 15.5% after 120-h-agitated culture. The glucose was used up by G. xylinus-pMV24-luxR at 72-h-agitated fermentation, which 12h earlier than the wild-type (WT). The total N-acylhomoserine lactones (AHL) content of the luxR-overexpressing strain and the WT strain attained 1367.9 ± 57.86mg/L and 842.9 ± 54.22mg/L, respectively. The C12-HSL and C14-HSL contents of G. xylinus-pMV24-luxR were 202 ± 21.66mg/L and 409.6 ± 0.91mg/L, which were significantly lower than that of WT. In contrast, C6-HSL showed opposite results. The difference of AHL content proved that overexpression of luxR improved the binding of AHL and showed preference for some specific AHL. The metabolic results demonstrated that upon glucose exhaustion, the consumption of gluconic acid was promoted by luxR overexpression, and the content of D- ( +)-trehalose, an antiretrograde metabolite, increased significantly. KEY POINTS: • The overexpression of luxR increased the yield of bacterial cellulose • The content of signal molecules was significantly different • Differential metabolites were involved in multiple metabolic pathways.

Encapsulation of Enzymes in Metal-Phenolic Network Capsules for the Trigger of Intracellular Cascade Reactions.

Nanoengineered capsules encapsulated with functional cargos (e.g., enzymes) are of interest for various applications including catalysis, bioreactions, sensing, and drug delivery. Herein, we report a facile strategy to engineer enzyme-encapsulated metal-phenolic network (MPN) capsules using enzyme-loaded zeolitic imidazolate framework nanoparticles (ZIF-8 NPs) as templates, which can be removed in a mild condition (e.g., ethylenediaminetetraacetic acid (EDTA) solution). The capsule size (from 250 nm to 1 μm) and thickness (from 9.8 to 33.7 nm) are well controlled via varying the template size and coating time, respectively. Importantly, MPN capsules encapsulated with enzymes (i.e., glucose oxidase) can trigger the intracellular cascade reaction via the exhaustion of glucose to produce H2O2 and subsequently generate toxic hydroxyl radicals (•OH) based on the Fenton reaction via the reaction between H2O2 and iron ions in MPN coatings. The intracellular cascade reaction for the generation of •OH is efficient to inhibit cancer cell viability, which is promising for the application in chemodynamic therapy.

Surfactin, a quorum sensing signal molecule, globally affects the carbon metabolism in Bacillus amyloliquefaciens

Surfactin, a quorum sensing signal molecule, is correlated with carbon metabolism in Bacillus amyloliquefaciens. In the present work, we found that mutation of srfA (ΔsrfA) led to an obviously changed carbon metabolism in B. amyloliquefaciens. Firstly, the PTS-glucose system was significantly increased as a feedback to glucose exhaustion. Secondly, the basic carbon metabolism such as glycolysis and TCA cycle was obviously weakened in ΔsrfA. Thirdly, the global regulator of CcpA (carbon catabolite protein A) and P ~ Ser46-HPr (seryl-phosphorylated form of histidine-containing protein) to mediate the CcpA-dependent CCR (carbon catabolite repression) were not increased, but the ability to use extracellular non- and less-preferred carbon sources was down-regulated in ΔsrfA. Fourthly, the carbon overflow metabolism such as biosynthesis of acetate was enhanced while biosynthesis of acetoin/2,3-butanediol and branched-chain amino acids were weakened in ΔsrfA. Finally, ΔsrfA could use most of non- and less-preferred carbon sources except for fatty acids, branched chain amino acids, and some organic acids (e.g. pyruvate, citrate and glutamate) after glucose exhaustion. Collectively, surfactin showed a global influence on carbon metabolism in B. amyloliquefaciens. Our studies highlighted a way to correlate quorum sensing with carbon metabolism via surfactin in Bacillus species.

Microorganisms maintain C:N stoichiometric balance by regulating the priming effect in long-term fertilized soils

Labile carbon (C) inputs affect the soil carbon:nitrogen (C:N) ratio and microbial stoichiometric homeostasis, which control the intensity and direction of the priming effect (PE). Here, we clarified how soil microorganisms regulate enzyme production and PE to maintain the C:N stoichiometric balance. Specifically, we conducted an incubation experiment by adding 13C-labeled glucose to four long-term fertilized paddy soils: no fertilization; fertilization with mineral nitrogen, phosphorus, and potassium (NPK); NPK combined with straw; and NPK with manure (NPKM). After glucose addition, the dissolved organic carbon-to-ammonium (DOC:NH4+) ratio (24–39) initially increased, but subsequently decreased after day 2 following glucose exhaustion. In parallel, the microbial C:N imbalance [(DOC:NH4+):(microbial biomass C:microbial biomass N)] rapidly decreased from day 2 (4.6–7.2) to day 20 (<0.5). Thus, microorganisms became C limited after 20 days of incubation. Excess C, resulting from glucose addition, increased N-hydrolase (chitinase) production and N mining from soil organic matter (SOM) through positive PEs. However, C hydrolase (β-1,4-glucosidase and β-xylosidase) activity increased, while that of N hydrolase (chitinase) decreased, following glucose exhaustion. Consequently, the C:N microbial biomass ratio increased as the DOC:NH4+ ratio decreased, leading to negative PEs. NPKM-fertilized soil had the largest cumulative PE (2.3% of soil organic carbon) because it had the highest microbial biomass and iron (Fe) reduction rate. Thus, this increased N mining from SOM maintained the microbial C:N stoichiometric balance. We concluded that soil microorganisms regulate C- and N-hydrolase production to control the intensity and direction of PE, maintaining the C:N stoichiometric balance in response to labile C inputs.

S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation

Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis). By our shedding assay of transforming growth factor α in HEK293A cells, ALESIA was determined to act as a sphingosine-1-phosphate receptor 3-G12-biased agonist that promotes nitric oxide production and oxidative stress. The oxidative stress triggered by ALESIA resulted in the exhaustion of glucose, cellular NADPH deficiency, and then cancer cell death. Intraperitoneal administration of ALESIA improved the survival of mice with peritoneally disseminated rhabdomyosarcoma, indicating its potential as a new type of anticancer drug for glucose starvation therapy.