Nutrient Starvation Conditions Research Articles

Lipidomic Analysis of Chlamydomonas reinhardtii under Nitrogen and Sulfur Deprivation.

Chlamydomonas reinhardtii accumulates lipids under complete nutrient starvation conditions while overall growth in biomass stops. In order to better understand biochemical changes under nutrient deprivation that maintain production of algal biomass, we used a lipidomic assay for analyzing the temporal regulation of the composition of complex lipids in C. reinhardtii in response to nitrogen and sulfur deprivation. Using a chip-based nanoelectrospray direct infusion into an ion trap mass spectrometer, we measured a diversity of lipid species reported for C. reinhardtii, including PG phosphatidylglycerols, PI Phosphatidylinositols, MGDG monogalactosyldiacylglycerols, DGDG digalactosyldiacylglycerols, SQDG sulfoquinovosyldiacylglycerols, DGTS homoserine ether lipids and TAG triacylglycerols. Individual lipid species were annotated by matching mass precursors and MS/MS fragmentations to the in-house LipidBlast mass spectral database and MS2Analyzer. Multivariate statistics showed a clear impact on overall lipidomic phenotypes on both the temporal and the nutrition stress level. Homoserine-lipids were found up-regulated at late growth time points and higher cell density, while triacyclglycerols showed opposite regulation of unsaturated and saturated fatty acyl chains under nutritional deprivation.

Differential Phosphatidylinositol-3-Kinase-Akt-mTOR Activation by Semliki Forest and Chikungunya Viruses Is Dependent on nsP3 and Connected to Replication Complex Internalization.

Many viruses affect or exploit the phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway, a crucial prosurvival signaling cascade. We report that this pathway was strongly activated in cells upon infection with the Old World alphavirus Semliki Forest virus (SFV), even under conditions of complete nutrient starvation. We mapped this activation to the hyperphosphorylated/acidic domain in the C-terminal tail of SFV nonstructural protein nsP3. Viruses with a deletion of this domain (SFV-Δ50) but not of other regions in nsP3 displayed a clearly delayed and reduced capacity of Akt stimulation. Ectopic expression of the nsP3 of SFV wild type (nsP3-wt), but not nsP3-Δ50, equipped with a membrane anchor was sufficient to activate Akt. We linked PI3K-Akt-mTOR stimulation to the intracellular dynamics of viral replication complexes, which are formed at the plasma membrane and subsequently internalized in a process blocked by the PI3K inhibitor wortmannin. Replication complex internalization was observed upon infection of cells with SFV-wt and SFV mutants with deletions in nsP3 but not with SFV-Δ50, where replication complexes were typically accumulated at the cell periphery. In cells infected with the closely related chikungunya virus (CHIKV), the PI3K-Akt-mTOR pathway was only moderately activated. Replication complexes of CHIKV were predominantly located at the cell periphery. Exchanging the hypervariable C-terminal tail of nsP3 between SFV and CHIKV induced the phenotype of strong PI3K-Akt-mTOR activation and replication complex internalization in CHIKV. In conclusion, infection with SFV but not CHIKV boosts PI3K-Akt-mTOR through the hyperphosphorylated/acidic domain of nsP3 to drive replication complex internalization. SFV and CHIKV are very similar in terms of molecular and cell biology, e.g., regarding replication and molecular interactions, but are strikingly different regarding pathology: CHIKV is a relevant human pathogen, causing high fever and joint pain, while SFV is a low-pathogenic model virus, albeit neuropathogenic in mice. We show that both SFV and CHIKV activate the prosurvival PI3K-Akt-mTOR pathway in cells but greatly differ in their capacities to do so: Akt is strongly and persistently activated by SFV infection but only moderately activated by CHIKV. We mapped this activation capacity to a region in nonstructural protein 3 (nsP3) of SFV and could functionally transfer this region to CHIKV. Akt activation is linked to the subcellular dynamics of replication complexes, which are efficiently internalized from the cell periphery for SFV but not CHIKV. This difference in signal pathway stimulation and replication complex localization may have implications for pathology.

Regulating the production of (R)-3-hydroxybutyrate in Escherichia coli by N or P limitation.

The chiral compound (R)-3-hydroxybutyrate (3HB) is naturally produced by many wild type organisms as the monomer for polyhydroxybutyrate (PHB). Both compounds are commercially valuable and co-polymeric polyhydroxyalkanoates have been used e.g., in medical applications for skin grafting and as components in pharmaceuticals. In this paper we investigate cultivation strategies for production of 3HB in the previously described E. coli strain AF1000 pJBGT3RX. This strain produces extracellular 3HB by expression of two genes from the PHB pathway of Halomonas boliviensis. H. boliviensis is a newly isolated halophile that forms PHB as a storage compound during carbon excess and simultaneous limitation of another nutrient like nitrogen and phosphorous. We hypothesize that a similar approach can be used to control the flux from acetyl-CoA to 3HB also in E. coli; decreasing the flux to biomass and favoring the pathway to the product. We employed ammonium- or phosphate-limited fed-batch processes for comparison of the productivity at different nutrient limitation or starvation conditions. The feed rate was shown to affect the rate of glucose consumption, respiration, 3HB, and acetic acid production, although the proportions between them were more difficult to affect. The highest 3HB volumetric productivity, 1.5 g L−1 h−1, was seen for phosphate-limitation.

Guttiferone K induces autophagy and sensitizes cancer cells to nutrient stress-induced cell death

BackgroundMedicinal plants have long been an excellent source of pharmaceutical agents. Autophagy, a catabolic degradation process through lysosomes, plays an important role in tumorigenesis and cancer therapy. PurposeThrough a screen designed to identify autophagic regulators from a library of natural compounds, we found that Guttiferone K (GUTK) can activate autophagy in several cancer cell lines. The objective of this study is to investigate the mechanism by which GUTK sensitizes cancer cells to cell death in nutrient starvation condition. MethodsCell death analysis was performed by propidium iodide staining with flow cytometry or Annexin V-FITC/PI staining assay. DCFH-DA staining was used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Cell viability was measured by MTT assay. ResultsExposure to GUTK was observed to markedly induce GFP-LC3 puncta formation and activate the accumulation of LC3-II and the degradation of p62 in HeLa cells, suggesting that GUTK is an autophagy inducer. Importantly, hydroxychloroquine, an autophagy inhibitor, was found to significantly prevent GUTK-induced cell death in nutrient starvation conditions, suggesting that the cell death observed is largely dependent on autophagy. We further provide evidence that GUTK inhibits Akt phosphorylation, thereby inhibiting the mTOR pathway in cancer cells during nutrient starvation. In addition, GUTK causes the accumulation of reactive oxygen species (ROS) and the phosphorylation of JNK in EBSS, which may mediate both autophagy and apoptosis. ConclusionThese data indicate that GUTK sensitizes cancer cells to nutrient stress-induced cell death though Akt/mTOR dependent autophagy pathway.

Uncovering miRNAs involved in crosstalk between nutrient deficiencies in Arabidopsis.

Integrating carbon (C), nitrogen (N), and sulfur (S) metabolism is essential for the growth and development of living organisms. MicroRNAs (miRNAs) play key roles in regulating nutrient metabolism in plants. However, how plant miRNAs mediate crosstalk between different nutrient metabolic pathways is unclear. In this study, deep sequencing of Arabidopsis thaliana small RNAs was used to reveal miRNAs that were differentially expressed in response to C, N, or S deficiency. Comparative analysis revealed that the targets of the differentially expressed miRNAs are involved in different cellular responses and metabolic processes, including transcriptional regulation, auxin signal transduction, nutrient homeostasis, and regulation of development. C, N, and S deficiency specifically induced miR169b/c, miR826 and miR395, respectively. In contrast, miR167, miR172, miR397, miR398, miR399, miR408, miR775, miR827, miR841, miR857, and miR2111 are commonly suppressed by C, N, and S deficiency. In particular, the miRNAs that are induced specifically by a certain nutrient deficiency are often suppressed by other nutrient deficiencies. Further investigation indicated that the modulation of nutrient-responsive miRNA abundance affects the adaptation of plants to nutrient starvation conditions. This study revealed that miRNAs function as important regulatory nodes of different nutrient metabolic pathways.

Polyhydroxyalkanoate (PHA) storage within a mixed-culture biomass with simultaneous growth as a function of accumulation substrate nitrogen and phosphorus levels

The response of a mixed-microbial-culture (MMC) biomass for PHA accumulation was evaluated over a range of relative nitrogen (N) and phosphorus (P) availabilities with respect to the supply of either complex (fermented whey permeate – FWP) or simpler (acetic acid) organic feedstocks. Fed-batch feed-on-demand PHA accumulation experiments were conducted where the feed N/COD and P/COD ratios were varied ranging from conditions of nutrient starvation to excess. A feast-famine enrichment (activated sludge) biomass, produced in a pilot-scale aerobic sequencing batch reactor on FWP and with a long history of stable PHA accumulation performance, was used for all the experiments as reference material. FWP with N/COD ratios of (2, 5, 15, 70 mg/g all with P/COD = 8 mg/g) as well as simulated FWP with nutrient starvation (N/COD = P/COD = 0) conditions were applied. For the acetic acid accumulations, nutrient starvation as well as N/COD variations (2.5, 5, 50 mg/g all with P/COD = 9 mg/g) and P/COD variations (0.5, 2, 9, 15 mg/g all with N/COD = 10 mg/g) were evaluated. An optimal range of combined N and P limitation with N/COD from 2 to 15 mg/g and P/COD from 0.5 to 3 mg/g was considered to offer consistent improvement of productivity over the case of nutrient starvation. Productivity increased due to active biomass growth of the PHA storing biomass without observed risk for a growth response overtaking PHA storage activity. PHA production with respect to the initial active biomass was significantly higher even in cases of excess nutrient additions when compared to the cases of nutrient starvation. The 24-h PHA productivities were enhanced as much as 4-fold from a base value of 1.35 g-PHA per gram initial active biomass with respect nutrient starvation feedstock. With or without nutrient loading the biomass consistently accumulated similar and significant PHA (nominally 60% g-PHA/g-VSS). Based on results from replicate experiments some variability in the extant biomass maximum PHA content was attributed to interpreted differences in the biomass initial physiological state and not due to changes in feedstock nutrient loading. We found that the accumulation process production rates for mixed cultures can be sustained long after the maximum PHA content of the biomass was reached. Within the specific context of the applied fed-batch feed-on-demand methods, active biomass growth was interpreted to have been largely restricted to the PHA-storing phenotypic fraction of the biomass. This study suggests practical prospects for mixed culture PHA production using a wide range of volatile fatty acid (VFA) rich feedstocks. Such VFA sources derived from residual industrial or municipal organic wastes often naturally contain associated nutrients ranging in levels from limitation to excess.

Seaweed sap: a sustainable way to improve productivity of maize in North-East India

The average productivity of Maize in the north-east hill region of India is very low (1.50 t/ha) mainly owing to cultivation under nutrient-starved conditions. Practical technologies have been developed to cultivate two commercially important seaweeds, viz. Kappaphycus alvarezii and Gracilaria edulis in tropical waters. The sap of these seaweeds has turned out to be a low-cost potent plant biostimulant when applied as foliar spray. A field experiment was conducted using different concentrations of both the seaweed saps in a research farm at Umiam, Meghalaya to study their impact on growth, yield and quality of maize. Results indicated that both the seaweed saps significantly improved the grain yield (10.5–13.1%), carbohydrate (12.3–17.4%) and protein content (4.8%) of maize over and above the control which received the recommended dose of fertilizers only. Thus, these seaweed saps are proved to be an eco-friendly means for enhancing maize productivity and quality in this economically backward region.

The viability and protein expression of Beijing/W lineage Mycobacterium tuberculosis circulating in Xinjiang, China.

Beijing/W lineage strains of Mycobacterium tuberculosis spread faster than other strains, tend to be more virulent and frequently associated with drug resistance. In this study, to distinguish the characteristics of Beijing/W lineage and non-Beijing/W lineage M. tuberculosis, we assessed the growth between the two groups under conditions of hypoxia, nutrient starvation, and intracellular growth in murine macrophages. We also examined the DNA, RNA, and protein levels of 5 major M. tuberculosis proteins, including HspX, Hsp65, 38 kDa, Ag85B, and MPT64 of the different types of strains by sequencing, quantitative RT-PCR, and Western blotting. The results showed that Beijing/W and non-Beijing/W lineage strains of M. tuberculosis have similar viability in ex vivo culture but differ in their ability to survive within macrophages, and the intracellular viability of the Beijing/W lineage strains was significantly more than the viability of the non-Beijing/W lineage strains at 2, 3, and 5 days after infection (P < 0.05). Psts1 and fbpB were expressed at statistically lower levels in Beijing/W lineage strains in their mRNA expression levels (P < 0.05). The expression of their corresponding 38 kDa and Ag85B was lower in the Beijing/W lineage strains than the non-Beijing/W lineage strains (P < 0.05). The expression of HspX and Hsp65 was higher in the Beijing/W lineage strains in their protein expression levels at 24 h after infection of RAW264.7 macrophages (P < 0.05). In conclusion, the increased viability of the Beijing/W lineage strains might be related to the expression levels of these proteins.

Rv0494 is a starvation-inducible, auto-regulatory FadR-like regulator from Mycobacterium tuberculosis.

Fatty acid metabolism plays an important role in the survival and pathogenesis of Mycobacterium tuberculosis. Lipids are assumed to be the major source of energy during dormancy. Here, we report the characterization of a starvation-inducible, lipid-responsive transcriptional regulator, Rv0494, divergently transcribed from the Rv0493c probable operon. The striking difference in the transcriptional regulatory apparatus between mycobacteria and other well-studied organisms, such as Escherichia coli, is the organization of mycobacterial promoters. Mycobacterial promoters have diverse architectures and most of these promoters function inefficiently in E. coli. In this study, we characterized the promoter elements of Rv0494 along with the sigma factors required for transcription initiation. Rv0494 promoter activity increased under nutrient starvation conditions and was transcribed via two promoters: the promoter proximal to the translational start site was active under standard growth conditions, whilst both promoters contributed to the increased activity seen during starvation, with the major contribution from the distal promoter. Furthermore, Rv0494 translation initiated at a codon located 9 bp downstream of the annotated start codon. Rv0494 bound to its upstream sequence to auto-regulate its own expression; this binding was responsive to long-chain fatty acyl-CoA molecules. We further report Rv0494-mediated transcriptional regulation of the Rv2326c gene - a probable transmembrane ATP-binding transporter encoding gene.

Plant peroxisomes are degraded by starvation-induced and constitutive autophagy in tobacco BY-2 suspension-cultured cells.

Very recently, autophagy has been recognized as an important degradation pathway for quality control of peroxisomes in Arabidopsis plants. To further characterize the role of autophagy in plant peroxisome degradation, we generated stable transgenic suspension-cultured cell lines of heterotrophic Nicotiana tabacum L. cv. Bright Yellow 2 expressing a peroxisome-targeted version of enhanced yellow fluorescent protein. Indeed, this cell line model system proved advantageous for detailed cytological analyses of autophagy stages and for quantification of cellular peroxisome pools under different culturing conditions and upon inhibitor applications. Complementary biochemical, cytological, and pharmacological analyses provided convincing evidence for peroxisome degradation by bulk autophagy during carbohydrate starvation. This degradation was slowed down by the inhibitor of autophagy, 3-methyladenine (3-MA), but the 3-MA effect ceased at advanced stages of starvation, indicating that another degradation mechanism for peroxisomes might have taken over. 3-MA also caused an increase particularly in peroxisomal proteins and cellular peroxisome numbers when applied under nutrient-rich conditions in the logarithmic growth phase, suggesting a high turnover rate for peroxisomes by basal autophagy under non-stress conditions. Together, our data demonstrate that a great fraction of the peroxisome pool is subject to extensive autophagy-mediated turnover under both nutrient starvation and optimal growth conditions. Our analyses of the cellular pool size of peroxisomes provide a new tool for quantitative investigations of the role of plant peroxisomes in reactive oxygen species metabolism.

Total synthesis of (±)-nicolaioidesin B via a highly regio- and diastereoselective Diels–Alder reaction

The total synthesis of (±)-nicolaioidesin B, a natural product that shows preferential cytotoxicity against pancreatic cancer cells under nutrient starvation conditions, is achieved. The key step is a thermally-induced, highly regio- and diastereoselective Diels–Alder reaction between (E)-N-methoxy-N-methylcinnamide and ocimene under solvent-free conditions.

Noxa upregulation by oncogenic activation of MEK/ERK through CREB promotes autophagy in human melanoma cells.

Reduction in the expression of the anti-survival BH3-only proteins PUMA and Bim is associated with the pathogenesis of melanoma. However, we have found that the expression of the other BH3-only protein Noxa is commonly upregulated in melanoma cells, and that this is driven by oncogenic activation of MEK/ERK. Immunohistochemistry studies showed that Noxa was expressed at higher levels in melanomas than nevi. Moreover, the expression of Noxa was increased in metastatic compared to primary melanomas, and in thick primaries compared to thin primaries. Inhibition of oncogenic BRAFV600E or MEK downregulated Noxa, whereas activation of MEK/ERK caused its upregulation. In addition, introduction of BRAFV600E increased Noxa expression in melanocytes. Upregulation of Noxa was due to a transcriptional increase mediated by cAMP responsive element binding protein, activation of which was also increased by MEK/ERK signaling in melanoma cells. Significantly, Noxa appeared necessary for constitutive activation of autophagy, albeit at low levels, by MEK/ERK in melanoma cells. Furthermore, it was required for autophagy activation that delayed apoptosis in melanoma cells undergoing nutrient deprivation. These results reveal that oncogenic activation of MEK/ERK drives Noxa expression to promote autophagy, and suggest that Noxa has an indirect anti-apoptosis role in melanoma cells under nutrient starvation conditions.

Autophagy in T-cell development, activation and differentiation.

Autophagy is a vital catabolic process for degrading bulky cytosolic contents, which cannot be resorbed via the proteasome. First described as a survival mechanism during nutrient starvation conditions, recent reports have demonstrated that autophagy supports metabolic functions of T cells at various stages of maturation and effector function. Autophagy is crucial for T-cell development at the precursor stage as self-renewability and quiescence of hematopoietic stem cells depend on autophagy of the mitochondria and the endoplasmic reticulum. Later, during development in the thymus, autophagy regulates peptide presentation in stromal cells and professional antigen-presenting cells, which mediate thymocyte selection. Furthermore, the metabolic changes when mature T cells enter the periphery and when they are activated are both dependent on autophagy. Lastly, autophagy prevents early aging and, thus, ensures maintenance of memory T cells.

Review of Sustainable Methane Mitigation and Biopolymer Production

Biological methane (CH4) mitigation combined with biopolymer (PHA-polyhydroxyalkaonate/PHB-polyhydroxybutyrate) production is a viable option in this fossil fuel-constrained era. Methantrophs are bacteria that can re-route CH4 into PHA/PHB under nutrient-starved conditions. However, most studies (up to 90%) investigated pure cultures to demonstrate capacity for PHA/PHB accumulation, which on an industrial scale is unlikely to be serviceable. Furthermore, commercialization is handicapped as there are still a number of unresolved issues which affect productivities, such as optimized process variables, characterization of robust consortia, and optimized reactor design. This review will summarize existing knowledge and highlight research needs to fast track methanotrophic PHA/PHB production from CH4.

Effect of nutrient starvation on nutrient uptake and extracellular polymeric substance for microalgae cultivation and separation

The purpose of the present study is to investigate the effects of nutrient starvation of microalgae on its nitrogen (N) and phosphorus (P) uptake, characteristics of extracellular polymeric substances (EPS), and algal sedimentation. An experiment was carried out by starving the wastewater-tolerant microalgae Chlorella sp. ADE4. The algal cultivation was put under various conditions of nutrient starvation in order to enhance nutrient removal and algal cell separation. The experimental results showed that 40 h of nutrient starvation prior to the cultivation did affect nutrient removal of Chlorella sp. ADE4. When using synthetic wastewater, the N-starved algae was the most effective in removing 82% of N in 48 h and 92% of P in 24 h. However, the starvation conditions did not cause noticeable removal improvement when microalgae were tested with real wastewater effluent. N and P removal efficiencies of 57 and 100%, respectively, were achieved in 48 h in real wastewater effluent. The lower N removal efficiency was caused by P limitation in the real sewage effluent. EPS were analyzed to evaluate if they play a role in algal cell agglomeration and subsequent microalgal separation. Carbohydrates and protein were indicated as major components in soluble and bound EPS. It was found that starvation of microalgae for 40 h could induce higher EPS production. Interestingly, the N-starved microalgae contained a large protein fraction in their EPS and low N content in their biomass. However, a significant correlation between EPS content and sedimentation efficiency was not observed in this study.

Autophagy promotes the survival and development of tumors by participating in the formation of vasculogenic mimicry

Autophagy, type II nonapoptotic cell death, is characterized by the formation of double-membrane cytosolic vesicles, the recycling of damaged cytoplasmic content and the maintenance of genetic stability and cellular homeostasis, under conditions of nutrient starvation, hypoxia or other therapeutic stress. In the present study, we comprehensively discuss its indispensable role in the formation of vasculogenic mimicry (VM), capillary-like tubes consisting of cells from the tumor itself instead of vascular endothelial cells. A short hairpin RNA (shRNA) to silence beclin1, an autophagy-specific gene, was designed, synthesized and subcloned into a vector to establish an autophagy-inhibited group, while negative control and blank groups were also established using human gastric cancer SGC7901 cells. We then investigated the VM formation ability of these three groups and detected changes in gene expression, survival and invasion correspondingly. The results showed that, following the formation of VM, the expression of pluripotent genes (c-myc, oct3/4, sox-2) and autophagy-specific genes (beclin1, ATG5, ATG7) were increased, which was consistent with the negative control cell group. However, the autophagy inhibited cell group did not form VM, and the expression of pluripotent genes was decreased. Moreover, the inhibition of autophagy reduced the survival and invasive ability of cancer cells under stress. We suggest that during the formation of VM, the stable expression of genes and the maintenance of survival and invasion are indispensable. Under a stress environment, autophagy is activated to maintain the stability of gene expression, maintain survival and invasive ability and facilitate VM formation, which can provide nutrients, oxygen and invasive channels to tumors, facilitating survival and development under stress.

Ypt1 suppresses defects of vesicle trafficking and autophagy in Ypt6 related mutants.

Ypt/Rab GTPases coordinately regulate vesicle trafficking in yeasts. Previously, Ypt1 was shown to suppress growth defects of Ypt6 and its related mutants (ypt6ts, ric1∆, rgp1∆, ric1∆rgp1∆), but the physiological role of this suppression has not been well studied. We have investigated the effects of Ypt1 on two major trafficking pathways, vesicle trafficking and autophagy, in Ypt6 related mutants. Ypt1 restores Snc1 transport to the plasma membrane via Golgi in the exocytic pathway in Ypt6 related mutants under nutrient rich conditions. Overexpression of Ypt1 suppresses autophagic defects under nutrient starvation conditions with increased GFP-Atg8 sorting to vacuoles and GFP-Atg8 to GFP conversion in Ypt6 related mutants. However, overexpression of Ypt1 does not restore Ypt6 intracellular localisation in rgp1∆ cells. We propose that vesicle trafficking and autophagy are closely connected processes, and Ypt1 and Ypt6 have some similar functions in both cellular processes.

Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the β′ subunit of RNA polymerase

Rifampicin resistance, a defining attribute of multidrug-resistant tuberculosis, is conferred by mutations in the β subunit of RNA polymerase. Sequencing of rifampicin-resistant (RIF-R) clinical isolates of Mycobacterium tuberculosis revealed, in addition to RIF-R mutations, enrichment of potential compensatory mutations around the double-psi β-barrel domain of the β' subunit comprising the catalytic site and the exit tunnel for newly synthesized RNA. Sequential introduction of the resistance allele followed by the compensatory allele in isogenic Mycobacterium smegmatis showed that these mutations respectively caused and compensated a starvation enhanced growth defect by altering RNA polymerase activity. While specific combinations of resistance and compensatory alleles converged in divergent lineages, other combinations recurred among related isolates suggesting transmission of compensated RIF-R strains. These findings suggest nutrient poor growth conditions impose larger selective pressure on RIF-R organisms that results in the selection of compensatory mutations in a domain involved in catalysis and starvation control of RNA polymerase transcription.

Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments

Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.

Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the beta ' subunit of RNA polymerase

Fitness costs of rifampicin resistance in Mycobacterium tuberculosis are amplified under conditions of nutrient starvation and compensated by mutation in the beta ' subunit of RNA polymerase