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Redox Biology May 2024High-risk human papillomaviruses (HPVs) are the causative agents of cervical cancer. Here, we report that HPV16 E6E7 promotes cervical cancer cell proliferation by...
High-risk human papillomaviruses (HPVs) are the causative agents of cervical cancer. Here, we report that HPV16 E6E7 promotes cervical cancer cell proliferation by activating the pentose phosphate pathway (PPP). We found that HPV16 E6 activates the PPP primarily by increasing glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. Mechanistically, HPV16 E6 promoted G6PD dimer formation by inhibiting its lactylation. Importantly, we suggest that G6PD K45 was lactylated during G6PD-mediated antioxidant stress. In primary human keratinocytes and an HPV-negative cervical cancer C33A cells line ectopically expressing HPV16 E6, the transduction of G6PD K45A (unable to be lactylated) increased GSH and NADPH levels and, correspondingly, decreasing ROS levels. Conversely, the re-expression of G6PD K45T (mimicking constitutive lactylation) in HPV16-positive SiHa cells line inhibited cell proliferation. In vivo, the inhibition of G6PD enzyme activity with 6-aminonicotinamide (6-An) or the re-expression of G6PD K45T inhibited tumor proliferation. In conclusion, we have revealed a novel mechanism of HPV oncoprotein-mediated malignant transformation. These findings might provide effective strategies for treating cervical and HPV-associated cancers.
Topics: Female; Humans; Human papillomavirus 16; Cell Line, Tumor; Uterine Cervical Neoplasms; Glucosephosphate Dehydrogenase; Pentose Phosphate Pathway; Papillomavirus Infections; Oncogene Proteins, Viral; Cell Proliferation
PubMed: 38457903
DOI: 10.1016/j.redox.2024.103108 -
Cells Dec 2023Tamoxifen-resistant breast cancer cells (TamR-BCCs) are characterized by an enhanced metabolic phenotype compared to tamoxifen-sensitive cells. FoxO3a is an important...
Tamoxifen-resistant breast cancer cells (TamR-BCCs) are characterized by an enhanced metabolic phenotype compared to tamoxifen-sensitive cells. FoxO3a is an important modulator of cell metabolism, and its deregulation has been involved in the acquisition of tamoxifen resistance. Therefore, tetracycline-inducible FoxO3a was overexpressed in TamR-BCCs (TamR/TetOn-AAA), which, together with their control cell line (TamR/TetOn-V), were subjected to seahorse metabolic assays and proteomic analysis. FoxO3a was able to counteract the increased oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) observed in TamR by reducing their energetic activity and glycolytic rate. FoxO3a caused glucose accumulation, very likely by reducing LDH activity and mitigated TamR biosynthetic needs by reducing G6PDH activity and hindering NADPH production via the pentose phosphate pathway (PPP). Proteomic analysis revealed a FoxO3a-dependent marked decrease in the expression of LDH as well as of several enzymes involved in carbohydrate metabolism (e.g., Aldolase A, LDHA and phosphofructokinase) and the analysis of cBioPortal datasets of BC patients evidenced a significant inverse correlation of these proteins and FoxO3a. Interestingly, FoxO3a also increased mitochondrial biogenesis despite reducing mitochondrial functionality by triggering ROS production. Based on these findings, FoxO3a inducing/activating drugs could represent promising tools to be exploited in the management of patients who are refractory to antiestrogen therapy.
Topics: Female; Humans; Breast Neoplasms; Drug Resistance, Neoplasm; MCF-7 Cells; Metabolic Reprogramming; Proteomics; Tamoxifen
PubMed: 38132097
DOI: 10.3390/cells12242777 -
Disease Markers 2023Dupilumab (DUP) is the first biological agent used treating atopic dermatitis (AD). Notwithstanding its high cost, the type of patient group for which the drug is...
Dupilumab (DUP) is the first biological agent used treating atopic dermatitis (AD). Notwithstanding its high cost, the type of patient group for which the drug is effective remains unclear. In this retrospective study, we aimed to identify novel and reliable biomarkers which can be measured before DUP administration and to predict the efficacy of DUP. Serum samples from 19 patients with AD treated with DUP were analysed by metabolome analysis using gas chromatography-mass spectrometry. Total 148 metabolites were detected, and the relative values of the metabolites were compared between the patient group that achieved 75% improvement in Eczema Area and Severity Index 16 weeks after administration of DUP (high responders: HR; = 11) and that did not (low responders: LR; = 8). The HR and LR groups had significant differences in the relative values of the eight metabolites (lactic acid, alanine, glyceric acid, fumaric acid, nonanoic acid, ribose, sorbitol, and ornithine), with ribose emerging as the best. Furthermore, we evaluated the serum concentrations of ribose and found that ribose may be a useful metabolite biomarker for predicting the efficacy of DUP in AD.
Topics: Humans; Dermatitis, Atopic; Retrospective Studies; Ribose; Treatment Outcome; Severity of Illness Index; Biomarkers
PubMed: 37946797
DOI: 10.1155/2023/9013756 -
Clinical Genitourinary Cancer Oct 2023Poly ADP-ribose polymerase inhibitors (PARPis) have clinical activity in several cancers. The rationale of their therapeutic use in urothelial cancer (UC) resides in the... (Review)
Review
Poly ADP-ribose polymerase inhibitors (PARPis) have clinical activity in several cancers. The rationale of their therapeutic use in urothelial cancer (UC) resides in the high homologous-recombination repair (HRR) deficiency (HRD) prevalence and potential cross-sensitivity with platinum-based chemotherapy (PBCT). This review aims to summarize and analyze trials exploring the activity of PARPis in UC, focusing on patients who may benefit from those agents, the best clinical setting for the treatment and the benefit of the association with immune-checkpoint inhibitors (ICIs). We included all the available trials analyzing the activity of PARPis in UC in neoadjuvant, adjuvant, first or subsequent lines, and maintenance setting. We included PARPis in monotherapy and in association with other agents. The results in the maintenance setting are intriguing: ATLANTIS trial showed signals of improved progression-free survival in patients with known HRR aberrations, although the Meet-URO12 trial, with its negative results, suggested the failure of clinical selection based on platinum sensitivity only. Single-agent PARPis in pretreated patients showed discouraging results in an unselected population of chemo-refractory patients. Concerning the association of PARPis with ICIs, several trials are exploring their role in platinum-naïve setting; the results in the advanced setting were globally negative. Prior selection of HRD status is essential to identify patients who might benefit from PARPis. The ideal clinical settings seem to be the maintenance treatment and the combination with ICIs in platinum-naïve patients. Definitive results of ongoing and further trials will delineate the position for PARPis, if any, in UC therapy.
Topics: Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Ribose; Ovarian Neoplasms; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms
PubMed: 37500375
DOI: 10.1016/j.clgc.2023.07.009 -
Frontiers in Immunology 2023Malaria remains a widespread health problem with a huge burden. Severe or complicated malaria is highly lethal and encompasses a variety of pathological processes,...
INTRODUCTION
Malaria remains a widespread health problem with a huge burden. Severe or complicated malaria is highly lethal and encompasses a variety of pathological processes, including immune activation, inflammation, and dysmetabolism. Previously, we showed that adrenal hormones, in particular glucocorticoids (GCs), play critical roles to maintain disease tolerance during infection in mice. Here, GC responses were studied in Cameroon in children with uncomplicated malaria (UM), severe malaria (SM) and asymptomatic controls (AC).
METHODS
To determine the sensitivity of leukocytes to GC signaling on a transcriptional level, we measured the induction of glucocorticoid induced leucine zipper (GILZ) and FK506-binding protein 5 (FKBP5) by GCs in human and murine leukocytes. Targeted tracer metabolomics on peripheral blood mononuclear cells (PBMCs) was performed to detect metabolic changes induced by GCs.
RESULTS
Total cortisol levels increased in patients with clinical malaria compared to AC and were higher in the SM versus UM group, while cortisol binding globulin levels were unchanged and adrenocorticotropic hormone (ACTH) levels were heterogeneous. Induction of both GILZ and FKBP5 by GCs was significantly reduced in patients with clinical malaria compared to AC and in malaria-infected mice compared to uninfected controls. Increased activity in the pentose phosphate pathway was found in the patients, but this was not affected by stimulation with physiological levels of hydrocortisone. Interestingly, hydrocortisone induced increased levels of cAMP in AC, but not in clinical malaria patients.
DISCUSSION
Altogether, this study shows that patients with SM have increased cortisol levels, but also a decreased sensitivity to GCs, which may clearly contribute to the severity of disease.
Topics: Humans; Child; Mice; Animals; Glucocorticoids; Hydrocortisone; Leukocytes, Mononuclear; Receptors, Glucocorticoid; Transcription Factors; Malaria
PubMed: 37492570
DOI: 10.3389/fimmu.2023.1187196 -
Communications Biology Jan 2024Our previous work has shown that D-ribose (RIB)-induced depressive-like behaviors in mice. However, the relationship between variations in RIB levels and depression as...
Our previous work has shown that D-ribose (RIB)-induced depressive-like behaviors in mice. However, the relationship between variations in RIB levels and depression as well as potential RIB participation in depressive disorder is yet unknown. Here, a reanalysis of metabonomics data from depressed patients and depression model rats is performed to clarify whether the increased RIB level is positively correlated with the severity of depression. Moreover, we characterize intestinal epithelial barrier damage, gut microbial composition and function, and microbiota-gut-brain metabolic signatures in RIB-fed mice using colonic histomorphology, 16 S rRNA gene sequencing, and untargeted metabolomics analysis. The results show that RIB caused intestinal epithelial barrier impairment and microbiota-gut-brain axis dysbiosis. These microbial and metabolic modules are consistently enriched in peripheral (fecal, colon wall, and serum) and central (hippocampus) glycerophospholipid metabolism. In addition, three differential genera (Lachnospiraceae_UCG-006, Turicibacter, and Akkermansia) and two types of glycerophospholipids (phosphatidylcholine and phosphatidylethanolamine) have greater contributions to the overall correlations between differential genera and glycerophospholipids. These findings suggest that the disturbances of gut microbiota by RIB may contribute to the onset of depressive-like behaviors via regulating glycerophospholipid metabolism, and providing new insight for understanding the function of microbiota-gut-brain axis in depression.
Topics: Humans; Animals; Mice; Rats; Brain-Gut Axis; Ribose; Lipid Metabolism; Gastrointestinal Microbiome; Glycerophospholipids
PubMed: 38195757
DOI: 10.1038/s42003-023-05759-1 -
Journal of Autoimmunity Nov 2023Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to...
Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161 NK cells, and expansion of CD38 Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.
Topics: TOR Serine-Threonine Kinases; Animals; Mice; Liver Cirrhosis; Transaldolase; Autoimmunity; Aryldialkylphosphatase; Autoantibodies; Humans; Mice, Knockout; Disease Models, Animal
PubMed: 37742509
DOI: 10.1016/j.jaut.2023.103112 -
Nature Metabolism Nov 2023Glucose is the primary source of energy for the brain; however, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP...
Glucose is the primary source of energy for the brain; however, it remains controversial whether, upon neuronal activation, glucose is primarily used by neurons for ATP production or if it is partially oxidized in astrocytes, as proposed by the astrocyte-neuron lactate shuttle model for glutamatergic neurons. Thus, an in vivo picture of glucose metabolism during cognitive processes is missing. Here, we uncover in Drosophila melanogaster a glia-to-neuron alanine transfer involving alanine aminotransferase that sustains memory formation. Following associative conditioning, glycolysis in glial cells produces alanine, which is back-converted into pyruvate in cholinergic neurons of the olfactory memory center to uphold their increased mitochondrial needs. Alanine, as a mediator of glia-neuron coupling, could be an alternative to lactate in cholinergic systems. In parallel, a dedicated glial glucose transporter imports glucose specifically for long-term memory, by directly transferring it to neurons for use by the pentose phosphate pathway. Our results demonstrate in vivo the compartmentalization of glucose metabolism between neurons and glial cells during memory formation.
Topics: Animals; Drosophila; Alanine; Drosophila melanogaster; Neuroglia; Glycolysis; Neurons; Glucose; Mitochondria; Lactic Acid
PubMed: 37932430
DOI: 10.1038/s42255-023-00910-y -
Journal of Bone Oncology Feb 2024Metabolic reprogramming is an adaptive response of tumour cells under hypoxia and low nutrition conditions. There is increasing evidence that glucose metabolism... (Review)
Review
Metabolic reprogramming is an adaptive response of tumour cells under hypoxia and low nutrition conditions. There is increasing evidence that glucose metabolism reprogramming can regulate the growth and metastasis of osteosarcoma (OS). Reprogramming in the progress of OS can bring opportunities for early diagnosis and treatment of OS. Previous research mainly focused on the glycolytic pathway of glucose metabolism, often neglecting the tricarboxylic acid cycle and pentose phosphate pathway. However, the tricarboxylic acid cycle and pentose phosphate pathway of glucose metabolism are also involved in the progression of OS and are closely related to this disease. The research on glucose metabolism in OS has not yet been summarized. In this review, we discuss the abnormal expression of key molecules related to glucose metabolism in OS and summarize the glucose metabolism related signaling pathways involved in the occurrence and development of OS. In addition, we discuss some of the targeted drugs that regulate glucose metabolism pathways, which can lead to effective strategies for targeted treatment of OS.
PubMed: 38288377
DOI: 10.1016/j.jbo.2024.100521 -
ELife Nov 2023Compelling evidence has accumulated on the role of oxidative stress on the endothelial cell (EC) dysfunction in acute coronary syndrome. Unveiling the underlying...
Compelling evidence has accumulated on the role of oxidative stress on the endothelial cell (EC) dysfunction in acute coronary syndrome. Unveiling the underlying metabolic determinants has been hampered by the scarcity of appropriate cell models to address cell-autonomous mechanisms of EC dysfunction. We have generated endothelial cells derived from thrombectomy specimens from patients affected with acute myocardial infarction (AMI) and conducted phenotypical and metabolic characterizations. AMI-derived endothelial cells (AMIECs) display impaired growth, migration, and tubulogenesis. Metabolically, AMIECs displayed augmented ROS and glutathione intracellular content, with a diminished glucose consumption coupled to high lactate production. In AMIECs, while PFKFB3 protein levels of were downregulated, PFKFB4 levels were upregulated, suggesting a shunting of glycolysis towards the pentose phosphate pathway, supported by upregulation of G6PD. Furthermore, the glutaminolytic enzyme GLS was upregulated in AMIECs, providing an explanation for the increase in glutathione content. Finally, AMIECs displayed a significantly higher mitochondrial membrane potential than control ECs, which, together with high ROS levels, suggests a coupled mitochondrial activity. We suggest that high mitochondrial proton coupling underlies the high production of ROS, balanced by PPP- and glutaminolysis-driven synthesis of glutathione, as a primary, cell-autonomous abnormality driving EC dysfunction in AMI.
Topics: Humans; Reactive Oxygen Species; Endothelial Cells; Metabolic Reprogramming; Oxidative Stress; Glycolysis; Glutathione; Myocardial Infarction; Phosphofructokinase-2
PubMed: 38014932
DOI: 10.7554/eLife.86260