Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the promotion of biosynthesis, ATP generation, ...detoxification and support of rapid proliferation. The pentose phosphate pathway (PPP) is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxidative branch and produces a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell proliferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous factors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.
The inflammasome has an essential function in innate immune, responding to a wide variety of stimuli. Here we show that the lncRNA Neat1 promotes the activation of several inflammasomes. Neat1 ...associates with the NLRP3, NLRC4, and AIM2 inflammasomes in mouse macrophages to enhance their assembly and subsequent pro-caspase-1 processing. Neat1 also stabilizes the mature caspase-1 to promote interleukin-1β production and pyroptosis. Upon stimulation with inflammasome-activating signals, Neat1, which normally resides in the paraspeckles, disassociates from these nuclear bodies and translocates to the cytoplasm to modulate inflammasome activation using above mechanism. Neat1 is also up-regulated under hypoxic conditions in a HIF-2α-dependent manner, mediating the effect of hypoxia on inflammasomes. Moreover, in the mouse models of peritonitis and pneumonia, Neat1 deficiency significantly reduces inflammatory responses. These results reveal a previously unrecognized role of lncRNAs in innate immunity, and suggest that Neat1 is a common mediator for inflammasome stimuli.
Luteolin (LTL) exerts remarkable tumor suppressive activity on various types of cancers, including non-small cell lung cancer (NSCLC). However, it is not completely understood whether the mechanism ...of its action against NSCLC is related to microRNAs (miRNAs). In the present study, we investigated the anti-tumor effects of LTL on NSCLC in vitro and in vivo. The results revealed that LTL could inhibit cell proliferation and induce apoptosis in both A549 and H460 cells. In a H460 xenograft tumor model of nude mice, LTL significantly suppressed tumor growth, inhibited cell proliferation, and induced apoptosis. miRNA microarray and quantitative PCR (qPCR) analysis indicated that miR-34a-5p was dramatically upregulated upon LTL treatment in tumor tissues. Furthermore, MDM4 was proved to be a direct target of miR-34a-5p by luciferase reporter gene assay. LTL treatment was associated with increased p53 and p21 protein expressions and decreased MDM4 protein expression in both NSCLC cells and tumor tissues. When miR-34a-5p was inhibited in vitro, the protein expressions of Bcl-2 and MDM4 were recovered, while that of p53, p21, and Bax were attenuated. Moreover, caspase-3 and caspase-9 activation induced by LHL treatment in vitro were also suppressed by miR-34a-5p inhibition. Overall, LTL could inhibit tumorigenesis and induce apoptosis of NSCLC cells by upregulation of miR-34a-5p via targeting MDM4. These findings provide novel insight into the molecular functions of LTL that suggest its potential as a therapeutic agent for human NSCLC.
We report that circACC1, a circular RNA derived from human ACC1, plays a critical role in cellular responses to metabolic stress. CircACC1 is preferentially produced over ACC1 in response to serum ...deprivation by the transcription factor c-Jun. It functions to stabilize and promote the enzymatic activity of the AMPK holoenzyme by forming a ternary complex with the regulatory β and γ subunits. The cellular levels of circACC1 modulate both fatty acid β-oxidation and glycolysis, resulting in profound changes in cellular lipid storage. In a tumor xenograft model, silencing or enforced expression of circACC1 resulted in growth inhibition and enhancement, respectively. Moreover, increased AMPK activation in colorectal cancer tissues was frequently associated with elevated circACC1 expression. We conclude that circACC1 serves as an economic means to elicit AMPK activation and moreover propose that cancer cells exploit circACC1 during metabolic reprogramming.
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•CircACC1, a circular RNA, acts as a component of the AMPK holoenzyme•CircACC1 assembles and stabilizes the AMPK complex and maintains basal activity•CircACC1 functions in metabolic adaptation responses to serum deprivation•Elevated circACC1 expression facilitates tumor development in vitro and in vivo
Li et al. demonstrate the mechanism and action of circACC1, a circular RNA derived from preACC1 mRNA, in directly promoting AMPK holoenzyme stability and activation. CircACC1 contributes to metabolic adaptation during serum deprivation by increasing glycolysis and beta-oxidation. Additionally, increased circACC1 may act as a tumor promoter in colorectal cancer.
Cancer cells consume large quantities of glucose and primarily use glycolysis for ATP production, even in the presence of adequate oxygen. This metabolic signature (aerobic glycolysis or the Warburg ...effect) enables cancer cells to direct glucose to biosynthesis, supporting their rapid growth and proliferation. However, both causes of the Warburg effect and its connection to biosynthesis are not well understood. Here we show that the tumour suppressor p53, the most frequently mutated gene in human tumours, inhibits the pentose phosphate pathway (PPP). Through the PPP, p53 suppresses glucose consumption, NADPH production and biosynthesis. The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. Tumour-associated p53 mutants lack the G6PD-inhibitory activity. Therefore, enhanced PPP glucose flux due to p53 inactivation may increase glucose consumption and direct glucose towards biosynthesis in tumour cells.
The c‐Myc proto‐oncogene is activated in more than half of all human cancers. However, the precise regulation of c‐Myc protein stability is unknown. Here, we show that the lncRNA‐MIF (c‐Myc ...inhibitory factor), a c‐Myc‐induced long non‐coding RNA, is a competing endogenous RNA for miR‐586 and attenuates the inhibitory effect of miR‐586 on Fbxw7, an E3 ligase for c‐Myc, leading to increased Fbxw7 expression and subsequent c‐Myc degradation. Our data reveal the existence of a feedback loop between c‐Myc and lncRNA‐MIF, through which c‐Myc protein stability is finely controlled. Additionally, we show that the lncRNA‐MIF inhibits aerobic glycolysis and tumorigenesis by suppressing c‐Myc and miR‐586.
Synopsis
The lncRNA‐MIF, induced by c‐Myc, acts as a ceRNA to attenuate the inhibitory effect of miR‐586 on the E3 ligase Fbxw7 and thus inhibits aerobic glycolysis and tumorigenesis by promoting c‐Myc degradation.
c‐Myc transcriptionally activates the lncRNA‐MIF, which competes with the Fbxw7 mRNA for miR‐586.
A feedback loop exists between c‐Myc and lncRNA‐MIF, through which c‐Myc protein stability is finely controlled.
LncRNA‐MIF inhibits aerobic glycolysis and tumorigenesis.
The lncRNA‐MIF, induced by c‐Myc, acts as a ceRNA to attenuate the inhibitory effect of miR‐586 on the E3 ligase Fbxw7 and thus inhibits aerobic glycolysis and tumorigenesis by promoting c‐Myc degradation.
Understanding soybean (Glycine max) domestication and improvement at a genetic level is important to inform future efforts to further improve a crop that provides the world's main source of oilseed. ...We detect 230 selective sweeps and 162 selected copy number variants by analysis of 302 resequenced wild, landrace and improved soybean accessions at >11× depth. A genome-wide association study using these new sequences reveals associations between 10 selected regions and 9 domestication or improvement traits, and identifies 13 previously uncharacterized loci for agronomic traits including oil content, plant height and pubescence form. Combined with previous quantitative trait loci (QTL) information, we find that, of the 230 selected regions, 96 correlate with reported oil QTLs and 21 contain fatty acid biosynthesis genes. Moreover, we observe that some traits and loci are associated with geographical regions, which shows that soybean populations are structured geographically. This study provides resources for genomics-enabled improvements in soybean breeding.
Quercetin (QCT) has been shown to have anticancer activities associated with apoptosis and autophagy induction. However, whether autophagy is functionally responsible for the inhibitory effect of QCT ...on hepatocellular carcinoma (HCC) remains elusive. This study aims to investigate if QCT inhibits HCC growth via autophagy induction. The in vitro experiments showed that QCT inhibited the growth of human HCC cells in dose- and time-dependent manners and had minimal cytotoxicity to normal hepatocytes. QCT increased both autophagosomes and autolysosomes in HCC cells, as determined by electron microscopy, GFP-RFP-LC3 fluorescence confocal microscopy and Western blot analysis of autophagy-related biomarkers. Functional assays using pathway-specific inhibitors, activators or siRNAs indicated that QCT stimulated autophagy in part via inhibiting the AKT/mTOR pathway and activating the MAPK pathways. Further functional experiments using autophagy inhibitors demonstrated that QCT induced apoptosis of HCC cells in part via stimulating autophagy. The in vivo studies showed that QCT significantly inhibited tumor growth associated with apoptosis induction and autophagy stimulation, and that inhibition of autophagy significantly alleviated the QCT effect on tumor growth inhibition and apoptosis induction. To the best of our knowledge, this is the first in vivo report to demonstrate that QCT inhibits HCC tumor growth and induces apoptosis in part via stimulation of autophagy. Our results provide strong experimental evidence to support that autophagy stimulation may be an important mechanism by which QCT induces cancer cell apoptosis, and pave the way for further clinical investigations by applying QCT or QCT-rich foods for HCC intervention.
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•A Nafion modified PEDOT–PIL functionalized MWCNTs composite coating was fabricated.•It showed high thermal stability and durability.•It exhibited high extraction selectivity and capacity to ...carbamate pesticides.
A poly(3,4-ethylenedioxythiophene)-ionic liquid polymer functionalized multiwalled carbon nanotubes (PEDOT-PIL/MWCNTs) composite solid-phase microextraction (SPME) coating was fabricated by electrodeposition. After being dipped in Nafion solution, a Nafion-modified coating was obtained. The outer layer Nafion played a crucial role in enhancing the durability and stability of the coating, thus it was robust enough for replicated extraction for at least 150 times without decrease of extraction performance. The Nafion-modified coating exhibited much higher sensitivity than commercial coatings for the direct extraction of carbamate pesticides in aqueous solutions, due to its strong hydrophobic effect and π–π affinity based enrichment. When it was used for the determination of carbamate pesticides in combination with gas chromatography-flame ionization detection, good linearity (correlation coefficients higher than 0.9981), low limits of detection (15.2–27.2ng/L) and satisfactory precision (relative standard deviation <8.2%, n=5) were achieved. The developed method was applied to the analysis of four carbamate pesticides in apple and lettuce samples, and acceptable recoveries (i.e. 87.5–106.5%) were obtained for the standard addition.
2-hydroxy-3-methylanthraquinone (HMA), an anthraquinone monomer in traditional Chinese medicine Hedyotis diffusa, has been reported to inhibit the growth of several types of cancer, but its effect on ...lung cancer has not been adequately investigated.
This study aimed to test the hypothesis that HMA inhibit the growth, migration, and invasion of lung cancer cells in part via downregulation of interleukin (IL)-6-induced JAK2/STAT3 pathway.
Growth and apoptosis of lung cancer cells were quantitated by CCK-8 assay and Annexin V-FITC/PI flow cytometric analysis, respectively. Migration and invasion of A549 cells were determined by wound-healing assay and transwell invasion assay, respectively. The effect of HMA on cytokines expression in A549 cells was evaluated by the cytokine antibody array assay. Gene expression and protein levels of related molecular markers were quantitated by real time-PCR and Western blot analysis, respectively.
HMA significantly inhibited IL-6-stimulated growth and colony formation of A549 cells, increased the number of apoptotic cells, and inhibited invasion associated with downregulation of expression of IL-6-induced MMP-1, MMP-2, and MMP-9 genes. IL-6 increased the levels of tyrosine phosphorylation of JAK2 and STAT3 in A549 cells, which was reversed by HMA treatment. In addition, HMA reduced the expression of a series of inflammation-related cytokines in A549 cells supernatant, including IL-6, G-CSF, IL-6R, IL-8, MCP-1, RANTES, TNF-α.
These results suggest that HMA may inhibit the growth and invasion of lung cancer cells in part via downregulation of IL-6-induced JAK2/STAT3 pathway.
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