Warburg Effect Research Articles

Forkhead box M1 mediates metabolic reprogramming in human colorectal cancer cells.

Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by upregulated glycolysis and/or fatty acid synthesis-related genes. The transcription factor forkhead box M1 (FOXM1) has been implicated in various cancers, contributing significantly to their development, including colorectal cancer (CRC), a major global health concern. Despite FOXM1's established role in cancer, its specific involvement in the Warburg effect and fatty acid biosynthesis in CRC remains unclear. We analyzed The Cancer Genome Atlas (TCGA) Colonic Adenocarcinoma and Rectal Adenocarcinoma (COADREAD) datasets to derive the correlation of the expression levels between FOXM1 and multiple genes and the survival prognosis based on FOXM1 expression. Using two human CRC cell lines, HT29 and HCT116, we conducted RNAi or plasmid transfection procedures, followed by a series of assays, including RNA extraction, quantitative real-time polymerase chain reaction, Western blot analysis, cell metabolic assay, glucose uptake assay, Oil Red O staining, cell viability assay, and immunofluorescence analysis. Higher expression levels of FOXM1 correlated with a poorer survival prognosis, and the expression of FOXM1 was positively correlated with glycolysis-related genes SLC2A1 and LDHA, de novo lipogenesis-related genes ACACA and FASN, and MYC. FOXM1 appeared to modulate AKT/mammalian target of rapamycin (mTOR) signaling, the expression of c-Myc, proteins related to glycolysis and fatty acid biosynthesis, and glucose uptake, as well as extracellular acidification rate in HT29 and HCT116 cells. In summary, FOXM1 plays a regulatory role in glycolysis, fatty acid biosynthesis, and cellular energy consumption, thereby influencing CRC cell growth and patient prognosis.NEW & NOTEWORTHY Transcription factor forkhead box M1 (FOXM1) regulates glycolysis, fatty acid biosynthesis, and cellular energy consumption, which, together, controls cell growth and patient prognosis in colorectal cancer (CRC).

The role of dysregulated metabolism and associated genes in gastric cancer initiation and development.

The review delves into the intricate interplay between metabolic dysregulation and the onset and progression of gastric cancer (GC), shedding light on a pivotal aspect of this prevalent malignancy. GC stands as one of the leading causes of cancer-related mortality worldwide, its trajectory influenced by a multitude of factors, among which metabolic dysregulation and aberrant gene expression play significant roles. The article navigates through the fundamental roles of metabolic dysregulation in the genesis of GC, unveiling phenomena such as aberrant glycolysis, epitomized by the Warburg effect, alongside anomalies in lipid and amino acid metabolism. It delineates how these disruptions fuel the cancerous process, facilitating uncontrolled cell proliferation and survival. Furthermore, the intricate nexus between metabolism and the vitality of GC cells is elucidated, underscoring the profound influence of metabolic reprogramming on tumor energy dynamics and the accrual of metabolic by-products, which further perpetuate malignant growth. A pivotal segment of the review entails an exploration of key metabolic-related genes implicated in GC pathogenesis. MYC and TP53 are spotlighted among others, delineating their pivotal roles in driving tumorigenesis through metabolic pathway modulation. These genetic pathways serve as critical nodes in the intricate network orchestrating GC development, providing valuable targets for therapeutic intervention. This review embarks on a forward-looking trajectory, delineating the potential therapeutic avenues stemming from insights into metabolic dysregulation in GC. It underscores the promise of targeted therapies directed towards specific metabolic pathways implicated in tumor progression, alongside the burgeoning potential of combination therapy strategies leveraging both metabolic and conventional anti-cancer modalities. In essence, this comprehensive review serves as a beacon, illuminating the intricate landscape of metabolic dysregulation in GC pathogenesis. Through its nuanced exploration of metabolic aberrations and their genetic underpinnings, it not only enriches our understanding of GC biology but also unveils novel therapeutic vistas poised to revolutionize its clinical management.

Time-dependent biochemical effects of the promising anticancer drug 3-bromopyruvate and its biochemical analogs pyruvate and lactate (Warburg effect) on C6 glioma-induced H2O2 production

Time-dependent biochemical effects of the promising anticancer drug 3-bromopyruvate and its biochemical analogs pyruvate and lactate (Warburg effect) on C6 glioma-induced H2O2 production

Hsa_circ_0007590/PTBP1 complex reprograms glucose metabolism by reducing the stability of m6A-modified PTEN mRNA in pancreatic ductal adenocarcinoma.

The role of circular RNAs (circRNAs) in glucose metabolism in pancreatic duct adenocarcinoma (PDAC) remains elusive. Through RNA sequencing of cells cultured under conditions of glucose deprivation, we identified hsa_circ_0007590. Sanger sequencing and RNase R and Act D treatments were performed to confirm the circular RNA features of hsa_circ_0007590. RNA in situ hybridization (RNA-ISH) and quantitative reverse transcription PCR (qRT-PCR) were used to estimate hsa_circ_0007590 expression in PDAC clinical specimens and cell lines. hsa_circ_0007590 expression was higher in PDAC patients and closely related to the clinicopathological characteristics of the disease. Cytoplasm‒nuclear fractionation and FISH assays demonstrated that hsa_circ_0007590 was located in the nucleus. Gain-of-function and loss-of-function assays were performed to assess the biological behaviors of PDAC cells. Seahorse XF assays were performed to validate the Warburg effect. hsa_circ_0007590 facilitated the proliferation, migration, and invasion of PDAC cells and promoted the Warburg effect. Mass spectrometry, RNA pulldown, RNA immunoprecipitation (RIP), RNA m6A quantification, m6A dot blot, MeRIP, and Western blotting were conducted to investigate the detailed mechanism through which hsa_circ_0007590 produces these effects. Mechanistically, hsa_circ_0007590 targeted PTBP1 and increased the expression of the m6A reader protein YTHDF2, leading to PTEN mRNA degradation and PI3K/AKT/mTOR pathway activation. Overall, hsa_circ_0007590, which targets PTBP1, reprograms glucose metabolism by attenuating the stability of m6A-modified PTEN mRNA and holds potential promise as a therapeutic target for PDAC.

Hippocampal warburg effect mediates hydrogen sulfide-ameliorated diabetes-associated cognitive dysfunction: Involving promotion of hippocampal synaptic plasticity

Our previous studies have reported that hydrogen sulfide (H2S) has ability to improve diabetes-associated cognitive dysfunction (DACD), but the exact mechanisms remain unknown. Recent research reveals that Warburg effect is associated with synaptic plasticity which plays a key role in cognition promotion. Herein, the present study was aimed to demonstrate whether hippocampal Warburg effect contributes to H2S-ameliorated DACD and further explore its potential mechanism. We found that H2S promoted the hippocampal Warburg effect and inhibited the OxPhos in the hippocampus of STZ-induced diabetic rats. It also improved the hippocampal synaptic plasticity in STZ-induced diabetic rats, as evidenced by the change of microstructures and the expression of different key-enzymes. Furthermore, inhibited hippocampal Warburg effect induced by DCA markedly abolished the improvement of H2S on synaptic plasticity in the hippocampus of STZ-induced diabetic rats. DCA blocked H2S-attenuated the cognitive dysfunction in STZ-induced diabetic rats, according to the Y-maze, Novel Objective Recognition, and Morris Water Maze tests. Collectively, these findings indicated that the hippocampal Warburg effect mediates H2S-ameliorated DACD by improving hippocampal synaptic plasticity.

Knockdown of α-Enolase (ENO1) to Suppress Glycolytic Pathway in Human Hepatocellular Carcinoma Cell Line (HepG2)

ABSTRACT Hepatocellular carcinoma therapies which are potentially curative depend on early diagnosis, but unfortunately only 20% is the 5-year survival rate of liver cancer despite of various treatment methods which progress continuously. Patients with hepatocellular carcinoma presenting with late stage disease despite established screening guidelines for patients at risk because of asymptomatic nature of this disease so finding effective treatments are imperative. Alpha-enolase has been noticed to be commonly over-expressed in tumors including hepatocellular carcinoma, it is one of the leading regulators of the Warburg effect, so plays an important role in carcinogenesis and tumor maintenance. In this study the cell line α-enolase short interference RNA was successfully constructed. In the α-enolase short interference RNA cell lines, messenger RNA and protein expression of α-enolase were lower than those in negative control and blank control groups. The pyruvate level was significantly inhibited, the proliferation ability was significantly suppressed. Our data provide strong evidence that α-enolase short interference RNA can efficiently suppress glycolysis pathway and thus the proliferation of Hep G2, which may provide a novel gene therapy for hepatocellular carcinoma.

Warburg Effect and Type II Glucose Transporter Inhibitors as a Potential Targeted Therapy for Liver Cancer: A Review

Warburg Effect and Type II Glucose Transporter Inhibitors as a Potential Targeted Therapy for Liver Cancer: A Review

Is Cancer Metabolism an Atavism?

The atavistic theory of cancer posits that cancer emerges and progresses through the reversion of cellular phenotypes to more ancestral types with genomic and epigenetic changes deactivating recently evolved genetic modules and activating ancient survival mechanisms. This theory aims at explaining the known cancer hallmarks and the paradox of cancer's predictable progression despite the randomness of genetic mutations. Lineweaver and colleagues recently proposed the Serial Atavism Model (SAM), an enhanced version of the atavistic theory, which suggests that cancer progression involves multiple atavistic reversions where cells regress through evolutionary stages, losing recently evolved traits first and reactivating primitive ones later. The Warburg effect, where cancer cells upregulate glycolysis and lactate production in the presence of oxygen instead of using oxidative phosphorylation, is one of the key feature of the SAM. It is associated with the metabolism of ancient cells living on Earth before the oxygenation of the atmosphere. This review addresses the question of whether cancer metabolism can be considered as an atavistic reversion. By analyzing several known characteristics of cancer metabolism, we reach the conclusion that this version of the atavistic theory does not provide an adequate conceptual frame for cancer research. Cancer metabolism spans a whole spectrum of metabolic states which cannot be fully explained by a sequential reversion to an ancient state. Moreover, we interrogate the nature of cancer metabolism and discuss its characteristics within the framework of the SAM.

Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis.

Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.

Opportunities and challenges of integrating HIF-1 into clinical practice for cancer treatment

The Warburg effect is one of the most studied mechanisms involved in cancer progression. It refers to the increased glucose uptake by cancer cells through aerobic glycolysis, instead of the Krebs cycle that takes place under normal conditions, followed by lactic acid fermentation. This mechanism is regulated by hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates the expression of genes responsible for the synthesis of proteins involved in glucose metabolism. Overexpression of HIF-1 has been linked to the Warburg effect. While several HIF-1-targeted strategies have been investigated, the majority have proven to be unsuccessful, especially in cases of aggressive tumors with hypoxic tumor microenvironments. Current strategies expand beyond conventional chemotherapeutic agents and include chemodynamic therapy, radiation therapy, and immune checkpoint molecules. The aim of this literature review is to highlight the implication of HIF-1 in the Warburg effect and the limitations that render cancer treatment less effective.

OCIAD2 promotes pancreatic cancer progression through the AKT signaling pathway

BackgroundOCIAD2（Ovarian carcinoma immunoreactive antigen-like protein 2） is a protein reported in various cancers. However, the role of OCIAD2 has not been explored in pan-cancer datasets. The purpose of this research lies in analyzing the expression level and prognostic-related value of OCIAD2 in different human cancers, as well as revealing the underlying mechanism in specific cancer type (pancreatic adenocarcinoma, PAAD). MethodsThe correlation between OCIAD2 expression level and clinical relevance in different human cancers was investigated from bioinformatical perspective (GTEx and TCGA). The OCIAD2 expression level and clinical significance in PAAD were explored in GEO datasets and tissue microarray. Functional experiments were used to determine the OCIAD2 cell functions in vitro and in vivo. GSEA, western blot and immunohistochemistry were used to uncover the potential mechanism. ResultsOCIAD2 expression level was closely correlated with clinical relevance in many cancer types through pan-cancer analysis, and we found OCIAD2 was highly expressed in PAAD and associated with poorer prognosis. OCIAD2 acted as the promotor of Warburg effect and influenced PAAD cells proliferation, migration and apoptosis. Mechanistically, OCIAD2 upregulation may boost glycolysis in PAAD via activating the AKT signaling pathway in PAAD. ConclusionsIn PAAD, OCIAD2 promotes Warburg effect via AKT signaling pathway and targeting cancer cells metabolic reprogramming could be a potential treatment.

Unprocessed snRNAs Are a Prognostic Biomarker and Correlate with a Poorer Prognosis in Colorectal Cancer.

The human Integrator complex is a set of 15 subunits that mediates processing of small nuclear RNAs (snRNAs), and which later participates in splicing messenger RNAs (mRNAs). In addition, it controls the pause and release of RNA polymerase II (RNA pol II) at specific gene promoters in response to growth factors. Mutations in Integrator-complex subunit 6 (INTS6) are associated with different types of tumors. However, the INTS6 gene product does not have a significant prognostic value as a biomarker for tumor progression. Here we show that Integrator-complex deregulation is involved in 8.3% of the colorectal cancer cases diagnosed from the population screen carried out in La Rioja (Spain) from the years 2017 to 2019. Lack of Integrator-complex function, measured by an increased level of unprocessed snRNA, is a prognostic biomarker and correlates with a poorer prognosis in colorectal-cancer patients. The transcriptomic profile of all analyzed colorectal tumors shows a strong alteration of the metabolic state of tumor cells, which compromises standard energy production through mitochondrial respiration, known as the Warburg effect. Furthermore, there is a significant upregulation of genes involved in extracellular matrix organization and collagen rearrangement. This is consistent with tissue reorganization in a growing tumor forming a polyp. Crossing the molecular data generated in this study with the follow-up of patients from population screening indicates that population screening combined with early typing of tumors appears to be the most efficient way to increase patient survival.

The role of lactate-induced protein lactylation in gliomas: implications for preclinical research and the development of new treatments.

The most prevalent primary brain tumors in adults are gliomas. In addition to insufficient therapeutic alternatives, gliomas are fatal mostly due to the rapid proliferation and continuous infiltration of tumor cells into the surrounding healthy brain tissue. According to a growing body of research, aerobic glycolysis, or the Warburg effect, promotes glioma development because gliomas are heterogeneous cancers that undergo metabolic reprogramming. Therefore, addressing the Warburg effect might be a useful therapeutic strategy for treating cancer. Lactate plays a critical role in reprogramming energy metabolism, allowing cells to rapidly access large amounts of energy. Lactate, a byproduct of glycolysis, is therefore present in rapidly proliferating cells and tumors. In addition to the protumorigenesis pathways of lactate synthesis, circulation, and consumption, lactate-induced lactylation has been identified in recent investigations. Lactate plays crucial roles in modulating immune processes, maintaining homeostasis, and promoting metabolic reprogramming in tumors, which are processes regulated by the lactate-induced lactylation of the lysine residues of histones. In this paper, we discuss the discovery and effects of lactylation, review the published studies on how protein lactylation influences cancer growth and further explore novel treatment approaches to achieve improved antitumor effects by targeting lactylation. These findings could lead to a new approach and guidance for improving the prognosis of patients with gliomas.

Differential Effect of Hyperglycemia on the Odds of Cancer Among the Adult Population of the United States.

Objective Accumulating evidence indicates a relationship between diabetes and cancer risk, with obesity, insulin resistance, and hyperglycemia being implicated as the major underlying pathogenetic mechanisms of increased cancer risk among people with diabetes. We aim to assess the differential effect of dysglycemia (prediabetes and diabetes) on the strength of association (odds) of cancer amongst the adult US diabetic population. Material and methods We analyzed data from the 1997-2013 National Health Interview Survey (NHIS) dataset, which applies a multistage area probability sampling design. We used descriptive statistics and logistic regression analyses to test the strengths of the association between diabetes, prediabetes, and cancer before and after adjusting for major risk factors for cancer, including age and body mass index (BMI). Results A total of 722,532 individuals were surveyed, with a mean age of 47.18 ±0.3 years (±SEM) and a BMI of 26.9 ±0.01 kg/m2. Between 1997 and 2013, BMI increased from 26.0 to 27.4 kg/m2, the diabetes rate increased from 4.1% to 7.6%, and associated cancer rates increased from 6.6% to 9.0%. Body mass index was 27.1 vs. 26.8 kg/m2, P < 0.01, for those with and without cancer, respectively. The unadjusted odds ratio for cancer was 1.92 (1.78-2.08) (95% CI) and 2.20 (2.13-2.27) for prediabetes and diabetes, respectively. After adjusting for age, BMI, race, and cigarette smoking, the odds ratio for cancer was 1.12 (1.03-1.22), P < 0.01, and 1.15 (1.11-1.18), P <0.01, for prediabetes and diabetes, respectively. Conclusion Among US adults, the increasing rate of diabetes over the years was associated with an increased rate of cancer. Diabetes and prediabetes have a graduated effect on cancer risk. While obesity is generally implicated as an underlying pathophysiologic link between diabetes and cancer, our study showed a modest difference in BMI between those with and without cancer. In addition, the effect of diabetes and prediabetes on the odds of cancer persisted after adjusting for BMI. These data collectively suggest that hyperglycemia is an attractive pathophysiologic mechanism that may play a role in increasing the odds of cancer among diabetic and prediabetic populations. Our study is consistent with the accumulating evidence implicating hyperglycemia in the pathogenesis of cancer, where glucose is used in PET scanning to detect cancer (the Warburg effect), and the ketogenic diet appears to be useful in cancer management, enhancing the effect of chemotherapeutic agents.

HOXC6-mediated transcriptional activation ofENO2 promotes oral squamous cell carcinoma progression through the Warburg effect.

Oral squamous cell carcinoma (OSCC) requires an in-depth exploration of its molecular mechanisms. The Warburg effect, along with the oncogenesenolase 2(ENO2) andhomeobox C6 (HOXC6), plays a central role in cancer. However, the specific interaction between ENO2 and HOXC6 in driving the Warburg effect and OSCC progression remains poorly understood. Through differential gene expression analysis in head and neck squamous cell carcinomas using Gene Expression Profiling Interactive Analysis, we identified upregulated ENO2 in OSCC. Silencing ENO2 in OSCC cells revealed its involvement in migration, invasion, and aerobic glycolysis of OSCC cells. Further exploration of ENO2's regulatory network identified HOXC6 as a potential transcriptional regulator. Subsequently, HOXC6 was silenced in OSCC cells, and expressions of ENO2 were assessed to validate its relationship with ENO2. Chromatin Immunoprecipitation and luciferase assays were utilized to investigate the direct transcriptional activation of ENO2 by HOXC6. A rescue assay co-overexpressing ENO2 and silencing HOXC6 in OSCC cells affirmed HOXC6's role in ENO2-associated glycolysis. High ENO2 expression in OSCC was validated through quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry analyses, which correlated with poor patient survival. Functional assays demonstrated that ENO2 silencing inhibited glycolysis and attenuated the aggressiveness of OSCC cells. In vivo studies confirmed the oncogenic role of ENO2 in OSCC growth. Notably, HOXC6 exhibited a positive correlation with ENO2 expression in clinical samples. Mechanistically, HOXC6 was identified as a direct transcriptional activator of ENO2, orchestrating the Warburg effect in OSCC cells. This study reveals the intricate link between HOXC6-mediated ENO2 transcriptional activation and the Warburg effect in OSCC, offering a potential therapeutic target for treating OSCC patients.

Exploring the Interplay between the Warburg Effect and Glucolipotoxicity in Cancer Development: A Novel Perspective on Cancer Etiology.

The Warburg effect, first observed by Otto Warburg in the 1920s, delineates a metabolic phenomenon in which cancer cells exhibit heightened glucose uptake and lactate production, even under normoxic conditions. This metabolic shift towards glycolysis, despite the presence of oxygen, fuels the energy demands of rapidly proliferating cancer cells. Dysregulated glucose metabolism, characterized by the overexpression of glucose transporters and the redirection of metabolic pathways towards glycolysis, lies at the crux of this metabolic reprogramming. Consequently, the accumulation of lactate as a byproduct contributes to the creation of an acidic tumor microenvironment, fostering tumor progression and metastasis. However, recent research, notably proposed by Maher Akl, introduces a novel perspective regarding the role of glycolipids in cancer metabolism. Akl's glucolipotoxicity hypothesis posits that aberrant glycolipid metabolism, specifically the intracellular buildup of glycolipids, significantly influences tumor initiation and progression. This hypothesis underscores the disruptive impact of accumulated glycolipids on cellular homeostasis, thereby activating oncogenic pathways and promoting carcinogenesis. This perspective aims to synthesize the intricate mechanisms underlying both the Warburg effect and glucolipotoxicity, elucidating their collective contributions to tumor growth and malignancy. By comprehensively understanding these metabolic aberrations, novel avenues for therapeutic intervention targeting the fundamental drivers of cancer initiation and progression emerge, holding promise for more efficacious treatment strategies in the future.

Importance of Michaelis Constants for Cancer Cell Redox Balance and Lactate Secretion-Revisiting the Warburg Effect.

Cancer cells metabolize a large fraction of glucose to lactate, even under a sufficient oxygen supply. This phenomenon-the "Warburg Effect"-is often regarded as not yet understood. Cancer cells change gene expression to increase the uptake and utilization of glucose for biosynthesis pathways and glycolysis, but they do not adequately up-regulate the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Thereby, an increased glycolytic flux causes an increased production of cytosolic NADH. However, since the corresponding gene expression changes are not neatly fine-tuned in the cancer cells, cytosolic NAD+ must often be regenerated by loading excess electrons onto pyruvate and secreting the resulting lactate, even under sufficient oxygen supply. Interestingly, the Michaelis constants (KM values) of the enzymes at the pyruvate junction are sufficient to explain the priorities for pyruvate utilization in cancer cells: 1. mitochondrial OXPHOS for efficient ATP production, 2. electrons that exceed OXPHOS capacity need to be disposed of and secreted as lactate, and 3. biosynthesis reactions for cancer cell growth. In other words, a number of cytosolic electrons need to take the "emergency exit" from the cell by lactate secretion to maintain the cytosolic redox balance.

DIPG-90. NON-INVASIVE METABOLIC IMAGING OF DIFFUSE MIDLINE GLIOMAS AND THEIR RESPONSE TO THERAPY

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring histone H3K27M mutations are devastating pediatric brain tumors. ONC201 is the first drug in decades to extend survival in DMG patients and is likely to be widely used for treatment of DMGs. However, magnetic resonance imaging (MRI), the gold standard for patient management, does not provide a reliable readout of response to therapy. The Warburg effect describes the propensity of tumor cells to increase glucose uptake and conversion to lactate. Deuterium metabolic imaging of the Warburg effect using [6,6’-2H]-glucose provides the unparalleled opportunity to obtain a biologically meaningful readout of treatment response. Therefore, the goal of this study was to assess the utility of [6,6’-2H]-glucose for DMG imaging. METHODS We performed expression profiling and deuterium metabolic imaging in patient-derived and syngeneic DMG models. RESULTS Our studies indicate that DMG cells upregulate key components of the Warburg effect, including SLC2A1, SLC2A3, HK2, PFKFB3, PGK1, and LDHA relative to normal astrocytes. Silencing the H3K27M mutation in DMG cells reduced glycolytic gene expression. Spatially resolved 2D chemical shift imaging at 3T showed that lactate produced from [6,6’-2H]-glucose was localized to tumor vs. normal brain in mice bearing intracranial tumors. ONC201 downregulated glycolytic gene expression in DMG cells, an effect that was accompanied by reduced lactate production from [6,6’-2H]-glucose. Importantly, lactate production from [6,6’-2H]-glucose was reduced following treatment with ONC201 in mice bearing intracranial tumors at 3T, at an early timepoint independent of MRI-detectable volumetric alterations and predictive of extended survival. CONCLUSIONS Our studies mechanistically link the H3K27M mutation with the Warburg effect. Importantly, they identify [6,6’-2H]-glucose as a novel contrast agent for visualizing the metabolic lesion and imaging early response to therapy in DMGs. Since [6,6’-2H]-glucose is a safe, orally administered agent, our studies have the potential to be rapidly translated to the clinic, where they will provide physicians with a much-needed tool to determine whether DMG patients are responding to therapy.

Prostate Cancer-Specific Lysine 53 Acetylation of Cytochrome c Drives Metabolic Reprogramming and Protects from Apoptosis in Intact Cells.

Cytochrome c (Cytc) is important for both mitochondrial respiration and apoptosis, both of which are altered in cancer cells that switch to Warburg metabolism and manage to evade apoptosis. We earlier reported that lysine 53 (K53) of Cytc is acetylated in prostate cancer. K53 is conserved in mammals that is known to be essential for binding to cytochrome c oxidase and apoptosis protease activating factor-1 (Apaf-1). Here we report the effects of this acetylation on the main functions of cytochrome c by expressing acetylmimetic K53Q in cytochrome c double knockout cells. Other cytochrome c variants analyzed were wild-type, K53R as a control that maintains the positive charge, and K53I, which is present in some non-mammalian species. Intact cells expressing K53Q cytochrome c showed 49% decreased mitochondrial respiration and a concomitant increase in glycolytic activity (Warburg effect). Furthermore, mitochondrial membrane potential was decreased, correlating with notably reduced basal mitochondrial superoxide levels and decreased cell death upon challenge with H2O2 or staurosporine. To test for markers of cancer aggressiveness and invasiveness, cells were grown in 3D spheroid culture. K53Q cytochrome c-expressing cells showed profoundly increased protrusions compared to WT, suggesting increased invasiveness. We propose that K53 acetylation of cytochrome c is an adaptive response that mediates prostate cancer metabolic reprogramming and evasion of apoptosis, which are two hallmarks of cancer, to better promote tumor survival and metastasis.

Unraveling the intricacies of cancer-associated fibroblasts: a comprehensive review on metabolic reprogramming and tumor microenvironment crosstalk.

Cancer-associated fibroblasts (CAFs) are crucial component of tumor microenvironment (TME) which undergo significant phenotypic changes and metabolic reprogramming, profoundly impacting tumor growth. This review delves into CAF plasticity, diverse origins, and the molecular mechanisms driving their continuous activation. Emphasis is placed on the intricate bidirectional crosstalk between CAFs and tumor cells, promoting cancer cell survival, proliferation, invasion, and immune evasion. Metabolic reprogramming, a cancer hallmark, extends beyond cancer cells to CAFs, contributing to the complex metabolic interplay within the TME. The 'reverse Warburg effect' in CAFs mirrors the Warburg effect, involving the export of high-energy substrates to fuel cancer cells, supporting their rapid proliferation. Molecular regulations by key players like p53, Myc, and K-RAS orchestrate this metabolic adaptation. Understanding the metabolic symbiosis between CAFs and tumor cells opens avenues for targeted therapeutic strategies to disrupt this dynamic crosstalk. Unraveling CAF-mediated metabolic reprogramming provides valuable insights for developing novel anticancer therapies. This comprehensive review consolidates current knowledge, shedding light on CAFs' multifaceted roles in the TME and offering potential targets for future therapies.