Metabolic Rewiring Of Cancer Cells Research Articles

Abstract 1794: PAF1 reprograms metabolism in pancreatic cancer by interacting with HIF1α

Abstract Background: Reprogrammed cellular metabolism has been refocused on in the past decade, as many cancer cells rewire various metabolic pathways to facilitate their survival, unlimited cell growth, and division. RNA Polymerase II-Associated Factor 1 (PAF1)/Pancreatic Differentiation 2 (PD2) is a core subunit of the human PAF1 Complex (PAF1C) that regulates the RNA polymerase II function during transcriptional elongation in normal cells; however, its overexpression has been implicated in promoting pancreatic tumorigenesis and metastasis through epigenetic regulation, chemoresistance, radioresistance and maintenance of cancer stem cells. While most of these studies have provided evidence of the multifunctional nature of PAF1/PD2 in PDAC progression, no study has investigated the role of PAF1/PD2 during the metabolic rewiring of cancer. Methods: In this study, we sought to examine the role of PAF1/PD2 in the metabolic rewiring of cancer cells in pancreatic ductal adenocarcinoma (PDAC) and decipher how PAF1/PD2 mediates this metabolic reprogramming in PDAC. Pancreatic cancer cell lines were transfected with shRNAs to knock down PAF1/PD2. Metabolic genes regulated by PAF1/PD2 were identified by qPCR and western blot upon PAF1/PD2 depletion. Metabolic assays were performed to investigate the role of PAF1/PD2. Immunoprecipitations identified proteins that interact with PAF1/PD2. Confocal microscopy confirmed the co-localization of PAF1/PD2 with its protein partners. We performed chromatin immunoprecipitation (ChIP) - Polymerase chain reaction to confirm the binding of the PAF1 sub-complex to its target gene. Results: Our results showed that pancreatic cancer cells depleted PAF1/PD2 downregulate genes involved in aerobic glycolysis compared to control cells. Also, the lactate release assay indicated that more lactate was produced in control cells than in cells with PAF1/PD2 knockdown. Interestingly, we identified that HIF1α interacts with PAF1, specifically in pancreatic cancer cells. PAF1 and HIF1α co-localization was observed in pancreatic cancer cell lines. We also observed that the PAF1/PD2- HIF1α complex bound to the promoter region of LDHA to regulate the expression of LDHA in pancreatic cancer cells, reprogramming the metabolism to utilize the aerobic glycolysis pathway preferentially. Conclusions: In conclusion, our study shows that PAF1/PD2 rewires the metabolism of PDAC by interacting with HIF1 α to regulate the expression of LDHA, which is the rate-limiting step of aerobic glycolysis. Citation Format: Ayoola O. Ogunleye, Neelanjana Gayen, Saravanakumar Marimuthu, Rama Krishna Nimmakayala, Sanchita Rauth, Zahraa Alsafwani, Jesse L. Cox, Surinder K. Batra, Moorthy P. Ponnusamy. PAF1 reprograms metabolism in pancreatic cancer by interacting with HIF1α [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1794.

Novel Fragment Inhibitors of PYCR1 from Docking-Guided X-ray Crystallography.

The proline biosynthetic enzyme Δ1-pyrroline-5-carboxylate (P5C) reductase 1 (PYCR1) is one of the most consistently upregulated enzymes across multiple cancer types and central to the metabolic rewiring of cancer cells. Herein, we describe a fragment-based, structure-first approach to the discovery of PYCR1 inhibitors. Thirty-seven fragment-like carboxylic acids in the molecular weight range of 143-289 Da were selected from docking and then screened using X-ray crystallography as the primary assay. Strong electron density was observed for eight compounds, corresponding to a crystallographic hit rate of 22%. The fragments are novel compared to existing proline analog inhibitors in that they block both the P5C substrate pocket and the NAD(P)H binding site. Four hits showed inhibition of PYCR1 in kinetic assays, and one has lower apparent IC50 than the current best proline analog inhibitor. These results show proof-of-concept for our inhibitor discovery approach and provide a basis for fragment-to-lead optimization.

Drivers of de novo Serine/Glycine synthesis in acute leukemia.

Cancer cells hijack metabolic pathways in order to provide themselves with building blocks to support their proliferation and survival. Upregulation and addiction to de novo serine/glycine synthesis is an example of metabolic rewiring in cancer cells whereby serine and glycine are synthesised via a side branch of glycolysis. In this review, we focus on upregulation of endogenous serine/glycine production in acute leukemia, namely T-cell acute leukemia (T-ALL) and acute myeloid leukemia (AML). Several genetic lesions directly driving the serine/glycine addiction in acute leukemia have been established. Additionally, indirect regulation of de novo serine/glycine synthesis is observed in acute leukemia.

The Pleiotropic Effects of Fumarate: From Mitochondrial Respiration to Epigenetic Rewiring and DNA Repair Mechanisms.

Tumor onset and its progression are strictly linked to its metabolic rewiring on the basis of the Warburg effect. In this context, fumarate emerged as a putative oncometabolite mediating cancer progression. Fumarate accumulation is usually driven by fumarate hydratase (FH) loss of function, the enzyme responsible for the reversible conversion of fumarate into malate. Fumarate accumulation acts as a double edge sword: on one hand it takes part in the metabolic rewiring of cancer cells, while on the other it also plays a crucial role in chromatin architecture reorganization. The latter is achieved by competing with a-ketoglutarate-dependent enzymes, eventually altering the cellular methylome profile, which in turn leads to its transcriptome modeling. Furthermore, in recent years, it has emerged that FH has an ability to recruit DNA double strand breaks. The accumulation of fumarate into damaged sites might also determine the DNA repair pathway in charge for the seizure of the lesion, eventually affecting the mutational state of the cells. In this work, we aimed to review the current knowledge on the role of fumarate as an oncometabolite orchestrating the cellular epigenetic landscape and DNA repair machinery.

MiR-494 induces metabolic changes through G6pc targeting and modulates sorafenib response in hepatocellular carcinoma

BackgroundMetabolic reprogramming is a well-known marker of cancer, and it represents an early event during hepatocellular carcinoma (HCC) development. The recent approval of several molecular targeted agents has revolutionized the management of advanced HCC patients. Nevertheless, the lack of circulating biomarkers still affects patient stratification to tailored treatments. In this context, there is an urgent need for biomarkers to aid treatment choice and for novel and more effective therapeutic combinations to avoid the development of drug-resistant phenotypes. This study aims to prove the involvement of miR-494 in metabolic reprogramming of HCC, to identify novel miRNA-based therapeutic combinations and to evaluate miR-494 potential as a circulating biomarker.MethodsBioinformatics analysis identified miR-494 metabolic targets. QPCR analysis of glucose 6-phosphatase catalytic subunit (G6pc) was performed in HCC patients and preclinical models. Functional analysis and metabolic assays assessed G6pc targeting and miR-494 involvement in metabolic changes, mitochondrial dysfunction, and ROS production in HCC cells. Live-imaging analysis evaluated the effects of miR-494/G6pc axis in cell growth of HCC cells under stressful conditions. Circulating miR-494 levels were assayed in sorafenib-treated HCC patients and DEN-HCC rats.ResultsMiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions. High miR-494 serum levels associated with sorafenib resistance in preclinical models and in a preliminary cohort of HCC patients. An enhanced anticancer effect was observed for treatment combinations between antagomiR-494 and sorafenib or 2-deoxy-glucose in HCC cells.ConclusionsMiR-494/G6pc axis is critical for the metabolic rewiring of cancer cells and associates with poor prognosis. MiR-494 deserves attention as a candidate biomarker of likelihood of response to sorafenib to be tested in future validation studies. MiR-494 represents a promising therapeutic target for combination strategies with sorafenib or metabolic interference molecules for the treatment of HCC patients who are ineligible for immunotherapy.

The "sweet" path to cancer: focus on cellular glucose metabolism.

The hypoxia-inducible factor-1α (HIF-1α), a key player in the adaptive regulation of energy metabolism, and the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), a critical regulator of glucose consumption, are the main drivers of the metabolic rewiring in cancer cells. The use of glycolysis rather than oxidative phosphorylation, even in the presence of oxygen (i.e., Warburg effect or aerobic glycolysis), is a major metabolic hallmark of cancer. Aerobic glycolysis is also important for the immune system, which is involved in both metabolic disorders development and tumorigenesis. More recently, metabolic changes resembling the Warburg effect have been described in diabetes mellitus (DM). Scientists from different disciplines are looking for ways to interfere with these cellular metabolic rearrangements and reverse the pathological processes underlying their disease of interest. As cancer is overtaking cardiovascular disease as the leading cause of excess death in DM, and biological links between DM and cancer are incompletely understood, cellular glucose metabolism may be a promising field to explore in search of connections between cardiometabolic and cancer diseases. In this mini-review, we present the state-of-the-art on the role of the Warburg effect, HIF-1α, and PKM2 in cancer, inflammation, and DM to encourage multidisciplinary research to advance fundamental understanding in biology and pathways implicated in the link between DM and cancer.

Contribution of Mitochondrial Activity to Doxorubicin-Resistance in Osteosarcoma Cells

Osteosarcoma is considered the most common bone tumor affecting children and young adults. The standard of care is chemotherapy; however, the onset of drug resistance still jeopardizes osteosarcoma patients, thus making it necessary to conduct a thorough investigation of the possible mechanisms behind this phenomenon. In the last decades, metabolic rewiring of cancer cells has been proposed as a cause of chemotherapy resistance. Our aim was to compare the mitochondrial phenotype of sensitive osteosarcoma cells (HOS and MG-63) versus their clones when continuously exposed to doxorubicin (resistant cells) and identify alterations exploitable for pharmacological approaches to overcome chemotherapy resistance. Compared with sensitive cells, doxorubicin-resistant clones showed sustained viability with less oxygen-dependent metabolisms, and significantly reduced mitochondrial membrane potential, mitochondrial mass, and ROS production. In addition, we found reduced expression of TFAM gene generally associated with mitochondrial biogenesis. Finally, combined treatment of resistant osteosarcoma cells with doxorubicin and quercetin, a known inducer of mitochondrial biogenesis, re-sensitizes the doxorubicin effect in resistant cells. Despite further investigations being needed, these results pave the way for the use of mitochondrial inducers as a promising strategy to re-sensitize doxorubicin cytotoxicity in patients who do not respond to therapy or reduce doxorubicin side effects.

Lactic acid fermentation: A maladaptive mechanism and an evolutionary throwback boosting cancer drug resistance

After four decades of research primarily focused on tumour genetics, the importance of metabolism in tumour biology is receiving renewed attention. Cancer cells undergo energy, biosynthetic and metabolic rewiring, which involves several pathways with a prevalent change from oxidative phosphorylation (OXPHOS) to lactic acid fermentation, known as the Warburg effect. During carcinogenesis, microenvironmental changes can trigger the transition from OXPHOS to lactic acid fermentation, an ancient form of energy supply, mimicking the behaviour of certain anaerobic unicellular organisms according to "atavistic" models of cancer. However, the role of this transition as a mechanism of cancer drug resistance is unclear. Here, we hypothesise that the metabolic rewiring of cancer cells to fermentation can be triggered, enhanced, and sustained by exposure to chronic or high-dose chemotherapy, thereby conferring resistance to drug therapy. We try to expand on the idea that metabolic reprogramming from OXPHOS to lactate fermentation in drug-resistant tumour cells occurs as a general phenotypic mechanism in any type of cancer, regardless of tumour cell heterogeneity, biodiversity, and genetic characteristics. This metabolic response may therefore represent a common feature in cancer biology that could be exploited for therapeutic purposes to overcome chemotherapy resistance, which is currently a major challenge in cancer treatment.

Oncometabolism: A Paradigm for the Metabolic Remodeling of the Failing Heart.

Heart failure is associated with profound alterations in cardiac intermediary metabolism. One of the prevailing hypotheses is that metabolic remodeling leads to a mismatch between cardiac energy (ATP) production and demand, thereby impairing cardiac function. However, even after decades of research, the relevance of metabolic remodeling in the pathogenesis of heart failure has remained elusive. Here we propose that cardiac metabolic remodeling should be looked upon from more perspectives than the mere production of ATP needed for cardiac contraction and relaxation. Recently, advances in cancer research have revealed that the metabolic rewiring of cancer cells, often coined as oncometabolism, directly impacts cellular phenotype and function. Accordingly, it is well feasible that the rewiring of cardiac cellular metabolism during the development of heart failure serves similar functions. In this review, we reflect on the influence of principal metabolic pathways on cellular phenotype as originally described in cancer cells and discuss their potential relevance for cardiac pathogenesis. We discuss current knowledge of metabolism-driven phenotypical alterations in the different cell types of the heart and evaluate their impact on cardiac pathogenesis and therapy.

Different Expression Patterns of Metabolic Reprogramming Proteins in Testicular Germ Cell Cancer

Metabolic reprogramming is an emerging hallmark of cancer, involving the overexpression of metabolism-related proteins, such as glucose and monocarboxylate transporters and intracellular glycolytic enzymes. The biology of testicular germ cell tumors (TGCTs) is very complex, and although their metabolic profile has been scantily explored, some authors have recently reported that the metabolic rewiring of cancer cells resulted in an association with aggressive clinicopathological characteristics. In this study we have investigated, by immunohistochemical analysis, the expression of key proteins sustaining the hyperglycolytic phenotype in pure seminoma (SE, nr. 35), pure embryonal carcinoma (EC, nr. 17) tissues samples, and normal testes (nr. 5). GLUT1, CD44, PFK-1, MCT1, MCT4, LDH-A, and PDH resulted in more expression in EC cells compared to SE cells. TOM20 was more expressed in SE than in EC. GLUT1, MCT1, and MCT4 expression showed a statistically significant association with SE histology, while for EC, the association resulted in being significant only for GLUT1 and MCT4. Finally, we observed that EC resulted as negative for p53, suggesting that the GLUT1 and MTC overexpression observed in EC could be also attributed to p53 downregulation. In conclusion, our findings evidenced that EC exhibits a higher expression of markers of active aerobic glycolysis compared to SE, suggesting that the aggressive phenotype is associated with a higher glycolytic rate. These data corroborate the emerging evidence on the involvement of metabolic reprogramming in testicular malignancies as well, highlighting that the metabolic players should be explored in the future as promising therapeutic targets.

FRUCTOSE DIET INDUCES A METABOLIC REPROGRAMMING TO ENHANCE TUMOR AGGRESSIVENESS

HCC is one of the main causes of cancer-related death worldwide and has third place in mortality. One of the main risk factors is metabolic-associated fatty liver disease (MAFLD), having hepatic steatosis, and related metabolic disorders. Mexican population has the highest obesity rate in both children and adults, and the consumption of hypercaloric diets has been related to that. Also, Mexico is in the top five countries with a higher fructose-enriched diet consumption and has been proved already the relation between fructose consumption and MAFLD. Likewise, fructose has been related to metabolic rewiring in transformed cells, enhancing aggressiveness and survival. To analyze fructose role on aggressiveness promotion of HCC cells. We used C57Bl/6J mice strain (both sex) with a high Fructose diet (Fru) (33% of fructose in the drinking water, ad libitum ). Fru supplementation started with 15 days-old mice, two days after DEN was injected (10 μg/Kg, i.p), and the treatment was ended 8 months later. The UAM ethics committee approved the protocol. In vitro studies were carried out with the Huh-7 HCC cell line and we evaluated metabolic and biochemical parameters. Tissue samples were analyzed by H&E. We observed that the fructose-enriched diet group mice presented fat accumulation in the hepatocytes and also areas with a greater inflammatory infiltrate (Fru). Mice in the fructose-enriched diet + DEN (Fru/HCC) group showed a marked difference between the tumor area and the surrounding tissue and an increase in the number of bile ducts, indicating liver tissue damage. Also, we analyzed the protein content of some lipogenic enzymes and noticed an increment in fatty acid synthase (Fasn) in Fru and Fru/HCC. Due to that, we analyzed if Fru treatment was inducing metabolic rewiring in transformed cells. We obtained metabolic changes in fructose-treated cells, reducing the glycolytic pathway and the traditional Warburg effect. Then we evaluated if the Huh-7 under a Fru treatment was more dependent on mitochondria or glycolysis ATP generation. We observed a reduction in proliferation under oligomycin treatment vs . 2-DG treatment. At least, we evaluated the pentose phosphate pathway (PPP) under a Fru treatment and obtained a higher glucose-6-phosphate dehydrogenase (G-6-P DH) activity with Fru vs. only glucose (Glc). Also, G-6-P DH had a more efficient activity in the presence of Fru because the time to reach the Vmax is lower vs . Glc. Fructose induces a metabolic rewiring in cancer cells to enhance ATP production, NADPH, and nucleotides to sustain the active lipid synthesis and proliferation. The fructose-enriched diets promote an aberrant lipogenic phenotype enhancing tumor aggressiveness. Conacyt, Froteras de la Ciencia 1320. The authors declare that there is no conflict of interest.

Structure-affinity relationships of reversible proline analog inhibitors targeting proline dehydrogenase.

Proline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the FAD-dependent oxidation of L-proline to Δ1-pyrroline-5-carboxylate. PRODH plays a central role in the metabolic rewiring of cancer cells, which has motivated the discovery of inhibitors. Here, we studied the inhibition of PRODH by 18 proline-like compounds to understand the structural and chemical features responsible for the affinity of the best-known inhibitor, S-(-)-tetrahydro-2-furoic acid (1). The compounds were screened, and then six were selected for more thorough kinetic analysis: cyclobutane-1,1-dicarboxylic acid (2), cyclobutanecarboxylic acid (3), cyclopropanecarboxylic acid (4), cyclopentanecarboxylic acid (16), 2-oxobutyric acid (17), and (2S)-oxetane-2-carboxylic acid (18). These compounds are competitive inhibitors with inhibition constants in the range of 1.4-6 mM, compared to 0.3 mM for 1. Crystal structures of PRODH complexed with 2, 3, 4, and 18 were determined. All four inhibitors bind in the proline substrate site, but the orientations of their rings differ from that of 1. The binding of 3 and 18 is accompanied by compression of the active site to enable nonpolar contacts with Leu513. Compound 2 is unique in that the additional carboxylate displaces a structurally conserved water molecule from the active site. Compound 18 also destabilizes the conserved water, but by an unexpected non-steric mechanism. The results are interpreted using a chemical double mutant thermodynamic cycle. This analysis revealed unanticipated synergism between ring size and hydrogen bonding to the conserved water. These structure-affinity relationships provide new information relevant to the development of new inhibitor design strategies targeting PRODH.

I\u03baB\u03b1 targeting promotes oxidative stress-dependent cell death

BackgroundOxidative stress is a hallmark of many cancers. The increment in reactive oxygen species (ROS), resulting from an increased mitochondrial respiration, is the major cause of oxidative stress. Cell fate is known to be intricately linked to the amount of ROS produced. The direct generation of ROS is also one of the mechanisms exploited by common anticancer therapies, such as chemotherapy.MethodsWe assessed the role of NFKBIA with various approaches, including in silico analyses, RNA-silencing and xenotransplantation. Western blot analyses, immunohistochemistry and RT-qPCR were used to detect the expression of specific proteins and genes. Immunoprecipitation and pull-down experiments were used to evaluate protein-protein interactions.ResultsHere, by using an in silico approach, following the identification of NFKBIA (the gene encoding IκBα) amplification in various cancers, we described an inverse correlation between IκBα, oxidative metabolism, and ROS production in lung cancer. Furthermore, we showed that novel IκBα targeting compounds combined with cisplatin treatment promote an increase in ROS beyond the tolerated threshold, thus causing death by oxytosis.ConclusionsNFKBIA amplification and IκBα overexpression identify a unique cancer subtype associated with specific expression profile and metabolic signatures. Through p65-NFKB regulation, IκBα overexpression favors metabolic rewiring of cancer cells and distinct susceptibility to cisplatin. Lastly, we have developed a novel approach to disrupt IκBα/p65 interaction, restoring p65-mediated apoptotic responses to cisplatin due to mitochondria deregulation and ROS-production.

Tumor Metabolic Reprogramming by Adipokines as a Critical Driver of Obesity-Associated Cancer Progression.

Adiposity is associated with an increased risk of various types of carcinoma. One of the plausible mechanisms underlying the tumor-promoting role of obesity is an aberrant secretion of adipokines, a group of hormones secreted from adipose tissue, which have exhibited both oncogenic and tumor-suppressing properties in an adipokine type- and context-dependent manner. Increasing evidence has indicated that these adipose tissue-derived hormones differentially modulate cancer cell-specific metabolism. Some adipokines, such as leptin, resistin, and visfatin, which are overproduced in obesity and widely implicated in different stages of cancer, promote cellular glucose and lipid metabolism. Conversely, adiponectin, an adipokine possessing potent anti-tumor activities, is linked to a more favorable metabolic phenotype. Adipokines may also play a pivotal role under the reciprocal regulation of metabolic rewiring of cancer cells in tumor microenvironment. Given the fact that metabolic reprogramming is one of the major hallmarks of cancer, understanding the modulatory effects of adipokines on alterations in cancer cell metabolism would provide insight into the crosstalk between obesity, adipokines, and tumorigenesis. In this review, we summarize recent insights into putative roles of adipokines as mediators of cellular metabolic rewiring in obesity-associated tumors, which plays a crucial role in determining the fate of tumor cells.

Contribution of the CK2 Catalytic Isoforms α and α' to the Glycolytic Phenotype of Tumor Cells.

CK2 is a Ser/Thr protein kinase overexpressed in many cancers. It is usually present in cells as a tetrameric enzyme, composed of two catalytic (α or α’) and two regulatory (β) subunits, but it is active also in its monomeric form, and the specific role of the different isoforms is largely unknown. CK2 phosphorylates several substrates related to the uncontrolled proliferation, motility, and survival of cancer cells. As a consequence, tumor cells are addicted to CK2, relying on its activity more than healthy cells for their life, and exploiting it for developing multiple oncological hallmarks. However, little is known about CK2 contribution to the metabolic rewiring of cancer cells. With this study we aimed at shedding some light on it, especially focusing on the CK2 role in the glycolytic onco-phenotype. By analyzing neuroblastoma and osteosarcoma cell lines depleted of either one (α) or the other (α’) CK2 catalytic subunit, we also aimed at disclosing possible pro-tumor functions which are specific of a CK2 isoform. Our results suggest that both CK2 α and α’ contribute to cell proliferation, survival and tumorigenicity. The analyzed metabolic features disclosed a role of CK2 in tumor metabolism, and suggest prominent functions for CK2 α isoform. Results were also confirmed by CK2 pharmacological inhibition. Overall, our study provides new information on the mechanism of cancer cells addiction to CK2 and on its isoform-specific functions, with fundamental implications for improving future therapeutic strategies based on CK2 targeting.

Targeting metabolic plasticity in glioma stem cells in vitro and in vivo through specific inhibition of c-Src by TAT-Cx43266-283.

BackgroundGlioblastoma is the most aggressive primary brain tumour and has a very poor prognosis. Inhibition of c-Src activity in glioblastoma stem cells (GSCs, responsible for glioblastoma lethality) and primary glioblastoma cells by the peptide TAT-Cx43266–283 reduces tumorigenicity, and boosts survival in preclinical models. Because c-Src can modulate cell metabolism and several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells, here we explored the inhibition of advantageous GSC metabolic plasticity by the c-Src inhibitor TAT-Cx43266-283.MethodsMetabolic impairment induced by the c-Src inhibitor TAT-Cx43266-283 in vitro was assessed by fluorometry, western blotting, immunofluorescence, qPCR, enzyme activity assays, electron microscopy, Seahorse analysis, time-lapse imaging, siRNA, and MTT assays. Protein expression in tumours from a xenograft orthotopic glioblastoma mouse model was evaluated by immunofluorescence.FindingsTAT-Cx43266–283 decreased glucose uptake in human GSCs and reduced oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on brain cell metabolism, including rat neurons, human and rat astrocytes, and human neural stem cells. TAT-Cx43266-283 impaired metabolic plasticity, reducing GSC growth and survival under different nutrient environments. Finally, GSCs intracranially implanted with TAT-Cx43266–283 showed decreased levels of important metabolic targets for cancer therapy, such as hexokinase-2 and GLUT-3.InterpretationThe reduced ability of TAT-Cx43266-283–treated GSCs to survive in metabolically challenging settings, such as those with restricted nutrient availability or the ever-changing in vivo environment, allows us to conclude that the advantageous metabolic plasticity of GSCs can be therapeutically exploited through the specific and cell-selective inhibition of c-Src by TAT-Cx43266-283.FundingSpanish Ministerio de Economía y Competitividad (FEDER BFU2015-70040-R and FEDER RTI2018-099873-B-I00), Fundación Ramón Areces. Fellowships from the Junta de Castilla y León, European Social Fund, Ministerio de Ciencia and Asociación Española Contra el Cáncer (AECC).

Breast Cancer Subtypes Underlying EMT-Mediated Catabolic Metabolism.

Efficient catabolic metabolism of adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) is essentially required for cancer cell survival, especially in metastatic cancer progression. Epithelial–mesenchymal transition (EMT) plays an important role in metabolic rewiring of cancer cells as well as in phenotypic conversion and therapeutic resistance. Snail (SNAI1), a well-known inducer of cancer EMT, is critical in providing ATP and NADPH via suppression of several gatekeeper genes involving catabolic metabolism, such as phosphofructokinase 1 (PFK1), fructose-1,6-bisphosphatase 1 (FBP1), and acetyl-CoA carboxylase 2 (ACC2). Paradoxically, PFK1 and FBP1 are counter-opposing and rate-limiting reaction enzymes of glycolysis and gluconeogenesis, respectively. In this study, we report a distinct metabolic circuit of catabolic metabolism in breast cancer subtypes. Interestingly, PFKP and FBP1 are inversely correlated in clinical samples, indicating different metabolic subsets of breast cancer. The luminal types of breast cancer consist of the pentose phosphate pathway (PPP) subset by suppression of PFKP while the basal-like subtype (also known as triple negative breast cancer, TNBC) mainly utilizes glycolysis and mitochondrial fatty acid oxidation (FAO) by loss of FBP1 and ACC2. Notably, PPP remains active via upregulation of TIGAR in the FBP1-loss basal-like subset, indicating the importance of PPP in catabolic cancer metabolism. These results indicate different catabolic metabolic circuits and thus therapeutic strategies in breast cancer subsets.

The impact of autophagy during the development and survival of glioblastoma.

Glioblastoma is the most common and aggressive adult brain tumour, with poor median survival and limited treatment options. Following surgical resection and chemotherapy, recurrence of the disease is inevitable. Genomic studies have identified key drivers of glioblastoma development, including amplifications of receptor tyrosine kinases, which drive tumour growth. To improve treatment, it is crucial to understand survival response processes in glioblastoma that fuel cell proliferation and promote resistance to treatment. One such process is autophagy, a catabolic pathway that delivers cellular components sequestered into vesicles for lysosomal degradation. Autophagy plays an important role in maintaining cellular homeostasis and is upregulated during stress conditions, such as limited nutrient and oxygen availability, and in response to anti-cancer therapy. Autophagy can also regulate pro-growth signalling and metabolic rewiring of cancer cells in order to support tumour growth. In this review, we will discuss our current understanding of how autophagy is implicated in glioblastoma development and survival. When appropriate, we will refer to findings derived from the role of autophagy in other cancer models and predict the outcome of manipulating autophagy during glioblastoma treatment.

Cancer aetiology and progression: The crucial link between genome, epigenome and metabolome

Genomic and metabolic profiles of cancer cells differ significantly from normal cells. Cancer cells utilise nutrients with an impaired metabolic process to maintain their high metabolic demands to adapt and proliferate. Metabolic rewiring in cancer cells has profound effects on the regulation of gene expression and vice versa. Genomic and metabolomic interactions are highly intertwined in both normal and cancer cells. Genomic components affect the metabolomic activities by modulating the expression of genes that regulate the metabolome. Inversely the metabolome, in turn, coordinates and provide a favourable microenvironment for genomic expression of metabolome regulating enzymes. The review aims to understand the link between genomic and metabolomic processes, their point of interaction, shared process, including dependent and independent networks in understanding cancer aetiology and progression. We systematically searched PubMed, Hinari, Google scholar and Nature journals to identify potentially relevant articles. We included reports that met the following criteria: (1) current knowledge on the cause of cancer as explained by genetic mutation, and (2) examine to what extent the mutation is determined by the metabolome. We also reviewed epigenetic aberration as hallmark of cancer aetiology. We discussed that the interaction between the genomic and metabolomic components is indispensable for the normal metabolic processes. Anything that alters the interplay of these processes will definitely cause impairment in the interaction and overall compromise in the entire genomic, metabolic, and cellular processes. Understanding the complex interaction between genome, epigenome, and metabolome is crucial to gain a greater insight into unravelling cancer pathogenesis and in the onset and progression of cancers and the potential of designing novel therapeutic strategies.

Multi-omics Reveal that c-Src Modulates the Mitochondrial Phosphotyrosine Proteome and Metabolism According to Nutrient Availability.

Src kinase family members, including c-Src, are involved in numerous signaling pathways and have been observed inside different cellular compartments. Notably, c-Src modulates carbohydrate and fatty acid metabolism and is involved in the metabolic rewiring of cancer cells. This kinase is found within mitochondria where it targets different proteins to impact on the organelle functions and overall metabolism. Surprisingly, no global metabolic characterization of Src has been performed although c-Src knock-out mice have been available for 30 years. Considering that c-Src is sensitive to various metabolites, c-Src might represent a crucial player in metabolic adjustments induced by nutrient stress. The aim of this work was to characterize the impact of c-Src on mitochondrial activity and overall metabolism using multi-omic characterization. Src+/+ and Src-/- mice were fed ad libitum or fasted during 24h and were then analyzed using multi-omics. We observed that deletion of c-Src is linked to lower phosphorylation of Y412-NDUFA8, inhibition of oxygen consumption and accumulation of metabolites involved in glycolysis, TCA cycle and amino acid metabolism in mice fed ad libitum. Finally, metabolomics and (phosphotyrosine) proteomics are differently impacted by Src according to nutrient availability. The findings presented here highlight that c-Src reduces mitochondrial metabolism and impacts the metabolic adjustment induced by nutrient stress.