Metformin turns off the metabolic switch of pancreatic cancer.
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ABSTRACT:
SUBMITTER: Deschenes-Simard X
PROVIDER: S-EPMC6932906 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
Publications
Metformin turns off the metabolic switch of pancreatic cancer.
Deschênes-Simard Xavier X Rowell Marie-Camille MC Ferbeyre Gerardo G
Aging 20191212 23
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Project description:Pancreatic ductal adenocarcinomas contain a subset of exclusively tumorigenic cancer stem cells (CSCs), which are capable of repopulating the entire heterogeneous cancer cell populations and are highly resistant to standard chemotherapy. Here we demonstrate that metformin selectively ablated pancreatic CSCs as evidenced by diminished expression of pluripotency-associated genes and CSC-associated surface markers. Subsequently, the ability of metformin-treated CSCs to clonally expand in vitro was irreversibly abrogated by inducing apoptosis. In contrast, non-CSCs preferentially responded by cell cycle arrest, but were not eliminated by metformin treatment. Mechanistically, metformin increased reactive oxygen species production in CSC and reduced their mitochondrial transmembrane potential. The subsequent induction of lethal energy crisis in CSCs was independent of AMPK/mTOR. Finally, in primary cancer tissue xenograft models metformin effectively reduced tumor burden and prevented disease progression; if combined with a stroma-targeting smoothened inhibitor for enhanced tissue penetration, while gemcitabine actually appeared dispensable.
| S-EPMC3799760 | biostudies-literature
Project description:Altered cellular energetic metabolism has recently emerged as important feature of neoplastic cells. Indeed, interfering with cancer cell metabolism might represent a suitable therapeutic strategy. In this study, we aimed to assess glucose metabolism activation in human lymphomas and evaluate how metformin can exert its action on lymphoma cells. We studied a large series of human lymphomas (N = 252) and an in vitro model of Burkitt lymphoma (BL) cells. We combined molecular biology techniques, including global gene expression profiling (GEP) analysis, quantitative PCR (qPCR) and Western blotting, and biochemical assays, aimed to assess pentose phosphate pathway, tricarboxylic acid (TCA) cycle, and aerobic glycolysis rates. We found that glucose metabolism is overall enhanced in most lymphoma subtypes, based on gene expression profiling (GEP), with general shift to aerobic glycolysis. By contrast, normal B cells only showed an overall increase in glucose usage during germinal center transition. Interestingly, not only highly proliferating aggressive lymphomas but also indolent ones, like marginal zone lymphomas, showed the phenomenon. Consistently, genes involved in glycolysis were confirmed to be overexpressed in BL cells by qPCR. Biochemical assays showed that while aerobic glycolysis is increased, TCA cycle is reduced. Finally, we showed that metformin can induce cell death in BL cells by stressing cellular metabolism through the induction of GLUT1, PKM2, and LDHA. In conclusion, we unveiled glucose metabolism abnormalities in human lymphomas and characterized the mechanism of action of metformin in Burkitt lymphoma model.
| S-EPMC8454268 | biostudies-literature
Project description:BackgroundProtein kinase D1 (PKD1) is a serine-threonine kinase that regulates various functions within the cell. Herein, we report the significance of PKD1 expression in glucose metabolism resulting in pancreatic cancer (PanCa) progression and chemo-resistance.MethodsPKD1 expression in PanCa was investigated by using immunohistochemistry. Functional and metabolic assays were utilised to analyse the effect of PKD1 expression/knockdown on associated cellular/molecular changes.ResultsPKD1 expression was detected in human pancreatic intraepithelial neoplasia lesions (MCS = 12.9; P < 0.0001) and pancreatic ductal adenocarcinoma samples (MCS = 15, P < 0.0001) as compared with faint or no expression in normal pancreatic tissues (MCS = 1.54; P < 0.0001). Our results determine that PKD1 enhances glucose metabolism in PanCa cells, by triggering enhanced tumorigenesis and chemo-resistance. We demonstrate that mTORC1 activation by PKD1 regulates metabolic alterations in PanCa cells. siRNA knockdown of Raptor or treatment with rapamycin inhibited PKD1-accelerated lactate production as well as glucose consumption in cells, which confirms the association of mTORC1 with PKD1-induced metabolic alterations.ConclusionThis study suggests a novel role of PKD1 as a key modulator of the glucose metabolism in PanCa cells accelerating tumorigenesis and chemo-resistance. The remodelling of PKD1-dysregulated glucose metabolism can be achieved by regulation of mTORC1 for development of novel therapeutic strategies.
| S-EPMC6964700 | biostudies-literature
Project description:UNLABELLED:Bacteria are extremely versatile organisms that rapidly adapt to changing environments. When bacterial cells switch from planktonic growth to biofilm, flagellum formation is turned off and the production of fimbriae and extracellular polysaccharides is switched on. BolA is present in most Gram-negative bacteria, and homologues can be found from proteobacteria to eukaryotes. Here, we show that BolA is a new bacterial transcription factor that modulates the switch from a planktonic to a sessile lifestyle. It negatively modulates flagellar biosynthesis and swimming capacity in Escherichia coli. Furthermore, BolA overexpression favors biofilm formation, involving the production of fimbria-like adhesins and curli. Our results also demonstrate that BolA is a protein with high affinity to DNA and is able to regulate many genes on a genome-wide scale. Moreover, we show that the most significant targets of this protein involve a complex network of genes encoding proteins related to biofilm development. Herein, we propose that BolA is a motile/adhesive transcriptional switch, specifically involved in the transition between the planktonic and the attachment stage of biofilm formation. IMPORTANCE:Escherichia coli cells possess several mechanisms to cope with stresses. BolA has been described as a protein important for survival in late stages of bacterial growth and under harsh environmental conditions. BolA-like proteins are widely conserved from prokaryotes to eukaryotes. Although their exact function is not fully established at the molecular level, they seem to be involved in cell proliferation or cell cycle regulation. Here, we unraveled the role of BolA in biofilm development and bacterial motility. Our work suggests that BolA actively contributes to the decision of bacteria to arrest flagellar production and initiate the attachment to form structured communities, such as biofilms. The molecular studies of different lifestyles coupled with the comprehension of the BolA functions may be an important step for future perspectives, with health care and biotechnology applications.
| S-EPMC4337573 | biostudies-literature
Project description:Bacteria are extremely versatile organisms which rapidly adapt to changing environments. When Escherichia coli cells switch from planktonic growth to biofilm, flagellum formation is turned off, and the production of fimbriae and extracellular polysaccharides is switched on. Here we show that BolA protein is a new bacterial transcription factor which modulates the switch from planktonic to sessile lifestyle. BolA negatively modulates flagella biosynthesis and thus swimming capacity. Furthermore, BolA overexpression favors biofilm formation and involvesinvolving fimbriae-like adhesins and curli production. Our results unraveled for the first time that BolA is a protein with high affinity to DNA, involved in the regulation of several genes of E. coli at a genome-wide scale level. Moreover, this observation further demonstrated that the most significant targets of this protein involved a complex network of genes encoding proteins extremely necessary in biofilm development processes. Herein we propose that BolA is a motile/adhesive transcriptional switch, specifically involved in the transition between the planktonic and the attachment stage of biofilm formation process.
2015-02-19 | GSE58509 | GEO
Project description:Bacteria are extremely versatile organisms which rapidly adapt to changing environments. When Escherichia coli cells switch from planktonic growth to biofilm, flagellum formation is turned off, and the production of fimbriae and extracellular polysaccharides is switched on. Here we show that BolA protein is a new bacterial transcription factor which modulates the switch from planktonic to sessile lifestyle. BolA negatively modulates flagella biosynthesis and thus swimming capacity. Furthermore, BolA overexpression favors biofilm formation and involvesinvolving fimbriae-like adhesins and curli production. Our results unraveled for the first time that BolA is a protein with high affinity to DNA, involved in the regulation of several genes of E. coli at a genome-wide scale level. Moreover, this observation further demonstrated that the most significant targets of this protein involved a complex network of genes encoding proteins extremely necessary in biofilm development processes. Herein we propose that BolA is a motile/adhesive transcriptional switch, specifically involved in the transition between the planktonic and the attachment stage of biofilm formation process. In the study presented here mRNA levels were analyzed in 2 different strains with different levels of BolA protein. Samples were measured at two differet growth phases and include 3 replicates of each.
2015-02-19 | E-GEOD-58509 | biostudies-arrayexpress
Project description:Bacteria are extremely versatile organisms which rapidly adapt to changing environments. When Escherichia coli cells switch from planktonic growth to biofilm, flagellum formation is turned off, and the production of fimbriae and extracellular polysaccharides is switched on. Here we show that BolA protein is a new bacterial transcription factor which modulates the switch from planktonic to sessile lifestyle. BolA negatively modulates flagella biosynthesis and thus swimming capacity. Furthermore, BolA overexpression favors biofilm formation and involvesinvolving fimbriae-like adhesins and curli production. Our results unraveled for the first time that BolA is a protein with high affinity to DNA, involved in the regulation of several genes of E. coli at a genome-wide scale level. Moreover, this observation further demonstrated that the most significant targets of this protein involved a complex network of genes encoding proteins extremely necessary in biofilm development processes. Herein we propose that BolA is a motile/adhesive transcriptional switch, specifically involved in the transition between the planktonic and the attachment stage of biofilm formation process.
2015-02-19 | GSE58623 | GEO
Project description:Bacteria are extremely versatile organisms which rapidly adapt to changing environments. When Escherichia coli cells switch from planktonic growth to biofilm, flagellum formation is turned off, and the production of fimbriae and extracellular polysaccharides is switched on. Here we show that BolA protein is a new bacterial transcription factor which modulates the switch from planktonic to sessile lifestyle. BolA negatively modulates flagella biosynthesis and thus swimming capacity. Furthermore, BolA overexpression favors biofilm formation and involvesinvolving fimbriae-like adhesins and curli production. Our results unraveled for the first time that BolA is a protein with high affinity to DNA, involved in the regulation of several genes of E. coli at a genome-wide scale level. Moreover, this observation further demonstrated that the most significant targets of this protein involved a complex network of genes encoding proteins extremely necessary in biofilm development processes. Herein we propose that BolA is a motile/adhesive transcriptional switch, specifically involved in the transition between the planktonic and the attachment stage of biofilm formation process. In the study presented here DNA enrichment was analyzed in 2 different strains, a strain containing bolA-3xflag-tag and a deletion mutant for this gene, which was used as the control sample.
2015-02-19 | E-GEOD-58623 | biostudies-arrayexpress
Project description:The tumor suppressor protein p53 induces apoptosis, cell cycle arrest, and DNA repair along with other functions in a transcription-dependent manner [Vousden, K. H. Cell 2000, 103(5), 691-694]. The selection of these functions depends on sequence-specific recognition of p53 to a target decameric sequence of gene promoters [Kitayner, M.; et al. Mol. Cell 2006, 22(6), 741-753]. Amino acid residues in p53 that directly bind to DNA were analyzed, and the replacement of A276 in p53 with selected amino acids elucidated its importance in promoter transcription. For most apoptotic and cell cycle gene promoters, position 9 of the target decameric sequence is a cytosine, while for DNA repair gene promoters, thymine is found instead. Therefore, selective binding to the cytosine at the ninth position may transcribe apoptotic gene promoters and thus can induce apoptosis and cell cycle arrest. Molecular modeling with PyMOL indicated that substitution of a hydrophilic residue, A276S, would prefer binding to cytosine at the ninth position of the target decameric sequence, whereas substitution of a hydrophobic residue (A276F) would fail to do so. Correspondingly, A276S demonstrated higher transcription of PUMA, PERP, and p21(WAF1/CIP1)gene promoters containing a cytosine at the ninth position and lower transcription of GADD45 gene promoter containing a thymine at the ninth position compared to wild-type p53. Cell cycle analysis showed that A276S maintained similar G1/G0 phase arrest as wild-type p53. Additionally, A276S induced higher apoptosis than wild-type p53 as measured by DNA segmentation and 7-AAD assay. Since the status of endogenous p53 can influence the activity of the exogenous p53, we examined the activity of A276S in HeLa cells (wild-type endogenous p53) in addition to T47D cells (mutated and mislocalized endogenous p53). The same apoptotic trend in both cell lines suggested A276S can induce cell death regardless of endogenous p53 status. Cell proliferation assay depicted that A276S efficiently reduced the viability of T47D cells more than wild-type p53 over time. We conclude that the predicted preferred binding of A276S to cytosine at the ninth position better transactivates a number of apoptotic gene promoters. Higher induction apoptosis than wild-type p53 makes A276S an attractive candidate for therapy to eradicate cancer.
| S-EPMC3658472 | biostudies-literature
Project description:Pancreatic β-cells become irreversibly damaged by long-term exposure to excessive glucose concentrations and lose their ability to carry out glucose stimulated insulin secretion (GSIS) upon damage. The β-cells are not able to control glucose uptake and they are therefore left vulnerable for endogenous toxicity from metabolites produced in excess amounts upon increased glucose availability. In order to handle excess fuel, the β-cells possess specific metabolic pathways, but little is known about these pathways. We present a study of β-cell metabolism under increased fuel pressure using a stable isotope resolved NMR approach to investigate early metabolic events leading up to β-cell dysfunction. The approach is based on a recently described combination of 13C metabolomics combined with signal enhanced NMR via dissolution dynamic nuclear polarization (dDNP). Glucose-responsive INS-1 β-cells were incubated with increasing concentrations of [U-13C] glucose under conditions where GSIS was not affected (2-8 h). We find that pyruvate and DHAP were the metabolites that responded most strongly to increasing fuel pressure. The two major divergence pathways for fuel excess, the glycerolipid/fatty acid metabolism and the polyol pathway, were found not only to operate at unchanged rate but also with similar quantity.
| S-EPMC7508987 | biostudies-literature