Gold Nanoparticle Detection with Two-Photon Excitation Fluorescence Lifetime Imaging of NAD(P)H in Cancer Cells: An Analytical Approach to Separate Nanoparticle and NAD(P)H Signals.

Untargeted metabolomics reveals alterations in the metabolic reprogramming of prostate cancer cells by double-stranded DNA-modified gold nanoparticles.

Sodium selenite inhibits cervical cancer progression via ROS-mediated suppression of glucose metabolic reprogramming

Crosstalk between metabolic and epigenetic modifications during cell carcinogenesis

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to sustain rapid proliferation, resist cell death, and adapt to varying microenvironmental conditions. This review elucidates the key mechanisms underlying metabolic reprogramming in cancer cells, including alterations in glucose metabolism, glutamine addiction, and lipid biosynthesis. A central feature of cancer metabolism is the Warburg effect, where cancer cells preferentially utilize aerobic glycolysis over oxidative phosphorylation, even in the presence of oxygen. This metabolic shift is driven by oncogenes and tumor suppressor genes, such as MYC and TP53, which modulate the expression and activity of enzymes involved in glycolysis and mitochondrial function. Additionally, cancer cells exhibit increased glutaminolysis, relying on glutamine as a carbon and nitrogen source to support anabolic processes and redox balance. Lipid metabolism is also reprogrammed, with enhanced de novo lipogenesis supplying membrane components and signaling molecules critical for tumor growth and survival. Understanding these metabolic alterations provides a basis for developing targeted therapies. Several therapeutic strategies have emerged, including inhibitors of key metabolic enzymes, such as hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and glutaminase. Metabolic interventions can disrupt the metabolic flexibility of cancer cells, sensitizing them to conventional therapies and overcoming resistance mechanisms. This review highlights the potential of metabolic targets in cancer treatment and emphasizes the need for personalized approaches considering tumor-specific metabolic profiles. Future research should focus on identifying biomarkers of metabolic vulnerabilities and developing combination therapies that exploit the intricate metabolic dependencies of cancer cells. Ultimately, targeting metabolic reprogramming holds promise for improving cancer prognosis and achieving more effective and durable therapeutic outcomes.

The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc. Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells. At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response. Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies.

Glucose and glutamine play a crucial role in the metabolic reprogramming of cancer cells. Proliferating cells metabolize glucose in the aerobic glycolysis for energy supply, and glucose and glutamine represent the primary sources of carbon atoms for the biosynthesis of nucleotides, amino acids, and lipids. Glutamine is also an important nitrogen donor for the production of nucleotides, amino acids, and nicotinamide. Several membrane receptors strictly control metabolic reprogramming in cancer cells and are considered new potential therapeutic targets. Formyl-peptide receptor 2 (FPR2) belongs to a small family of GPCRs and is implicated in many physiopathological processes. Its stimulation induces, among other things, NADPH oxidase-dependent ROS generation that, in turn, contributes to intracellular signaling. Previously, by phosphoproteomic analysis, we observed that numerous proteins involved in energetic metabolism are uniquely phosphorylated upon FPR2 stimulation. Herein, we investigated the role of FPR2 in cell metabolism, and we observed that the concentrations of several metabolites associated with the pentose phosphate pathway (PPP), tricarboxylic acid cycle, nucleotide synthesis, and glutamine metabolism, were significantly enhanced in FPR2-stimulated cells. In particular, we found that the binding of specific FPR2 agonists: (i) promotes NADPH production; (ii) activates the non-oxidative phase of PPP; (iii) induces the expression of the ASCT2 glutamine transporter; (iv) regulates oxidative phosphorylation; and (v) induces the de novo synthesis of pyrimidine nucleotides, which requires FPR2-dependent ROS generation.

Metabolic reprogramming in cancer is considered to be one of the most important hallmarks to drive proliferation, angiogenesis, and invasion. AMP-activated protein kinase activation is one of the established mechanisms for metformin’s anti-cancer actions. However, it has been suggested that metformin may exert antitumoral effects by the modulation of other master regulators of cellular energy. Here, based on structural and physicochemical criteria, we tested the hypothesis that metformin may act as an antagonist of L-arginine metabolism and other related metabolic pathways. First, we created a database containing different L-arginine-related metabolites and biguanides. After that, comparisons of structural and physicochemical properties were performed employing different cheminformatic tools. Finally, we performed molecular docking simulations using AutoDock 4.2 to compare the affinities and binding modes of biguanides and L-arginine-related metabolites against their corresponding targets. Our results showed that biguanides, especially metformin and buformin, exhibited a moderate-to-high similarity to the metabolites belonging to the urea cycle, polyamine metabolism, and creatine biosynthesis. The predicted affinities and binding modes for biguanides displayed good concordance with those obtained for some L-arginine-related metabolites, including L-arginine and creatine. In conclusion, metabolic reprogramming in cancer cells by metformin and biguanides may be also driven by metabolic disruption of L-arginine and structurally related compounds.

The targeting of “glycolytic addiction” in cancer has been an attractive proposition since the time the Warburg effect was reported in the 1940s. However this has not been successful in the clinic thus far, as the outcome of numerous clinical trials with glycolytic inhibitors has not been encouraging either due to minimal efficacy at lower tolerable doses or undue toxicity at higher effective doses. We hypothesized that the extensive cross-talk between the glycolytic pathway and other networks of cellular metabolism offers prospective avenues through which cancer cells can escape inhibition of any one node in the glycolytic pathway. By continuously exposing several glycolysis-addicted cancer cell lines to the glycolytic inhibitor 2-deoxyglucose (2-DG), we have generated derivative Glycolysis Independent lines (GIs) lines with substantially reduced glycolytic dependency. We also employed 2-DG innately resistant glycolysis independent lines to compare and contrast with the derivative GI lines. GIs, both acquired and innate, equally exhibit glycolysis independence to the knockdown of the glycolytic enzyme glucose-6-phosphate isomerase (PGI), which is blocked by 2-DG. GIs, but not their parental counterparts, exhibit elevated OX-PHOS rates to compensate for the reduced glycolytic rates. Steady state and targeted flux analyses revealed extensive metabolic reprogramming in GIs: 1. GIs increasingly utilize glutamine to feed the TCA cycle, OXPHOS and pyrimidine synthesis. 2. GIs effectively circumvent 2-DG-induced block downstream of glucose-6 phosphate (G6P) by shunting G6P through the pentose phosphate pathway back into the glycolysis, thereby generating acetyl CoA for the TCA cycle and for fatty acid biosynthesis. We determined that the S6 kinase axis of the mTOR pathway critically underlies the metabolic re-wiring of GIs, both acquired and innate. Pharmacologically targeting either S6K1 or OX-PHOS or glutaminase (the rate-limiting enzyme for glutamine breakdown in the mitochondria) not only re-sensitized GIs to 2-DG, but also pre-empted the acquisition of resistance to glycolytic inhibitors. Interestingly we were also able to re-sensitize GIs (both acquired and innate) to PGI knockdown by pharmacologically targeting either S6K1 or OXPHOS indicating the robustness of our models. Furthermore, the combination of either everolimus (clinically approved mTOR inhibitor) or phenformin (mitochondrial complex I inhibitor) with the inducible knockdown of PGI significantly reduced tumor volumes in both the acquired and innate GI line xenograft models whereas either of the drugs or PGI knockdown alone was ineffective in reducing tumor burden. Taken together, our findings suggest that cancer cells can acquire resistance to glycolytic inhibitors via mTOR/S6K pathway-mediated re-wiring of glycolytic and mitochondrial metabolic networks. Therefore, the combined targeting of glycolysis and mTOR/S6K1 or mitochondrial metabolism may be a viable therapeutic strategy to reduce tumor burden in patients across various indications. Citation Format: Raju Pusapati, Min Gao, Anneleen Daemen, Georgia Hatzivassiliou, Jeffrey Settleman. mTOR/S6K pathway-dependent metabolic reprogramming in cancer cells mediates resistance to glycolytic inhibitors. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B02.

Metabolic reprogramming in cancer cells involves changes in glucose metabolism, glutamine utilization, and lipid production, as well as promoting increased cell proliferation, survival, and immune resistance by altering the tumor microenvironment. Our study analyzes metabolic reprogramming in neoplastically transformed cells, focusing on changes in glucose metabolism, glutaminolysis, and lipid synthesis. Moreover, we discuss the therapeutic potential of targeting cancer metabolism, focusing on key enzymes involved in glycolysis, the pentose phosphate pathway, and amino acid metabolism, including lactate dehydrogenase A, hexokinase, phosphofructokinase and others. The review also highlights challenges such as metabolic heterogeneity, adaptability, and the need for personalized therapies to overcome resistance and minimize adverse effects in cancer treatment. This review underscores the significance of comprehending metabolic reprogramming in cancer cells to engineer targeted therapies, personalize treatment methodologies, and surmount challenges, including metabolic plasticity and therapeutic resistance.

MicroRNAs (miRNAs) are involved in the regulation of mitochondrial function and homeostasis, and in the modulation of cell metabolism, by targeting known oncogenes and tumor suppressor genes of metabolic-related signaling pathways involved in the hallmarks of cancer. This systematic review focuses on articles describing the role, association, and/or involvement of miRNAs in regulating the mitochondrial function and metabolic reprogramming of cancer cells. Following the PRISMA guidelines, the articles reviewed were published from January 2010 to September 2022, with the search terms “mitochondrial microRNA” and its synonyms (mitochondrial microRNA, mitochondrial miRNA, mito microRNA, or mitomiR), “reprogramming metabolism,” and “cancer” in the title or abstract). Thirty-six original research articles were selected, revealing 51 miRNAs with altered expression in 12 cancers: bladder, breast, cervical, colon, colorectal, liver, lung, melanoma, osteosarcoma, pancreatic, prostate, and tongue. The actions of miRNAs and their corresponding target genes have been reported mainly in cell metabolic processes, mitochondrial dynamics, mitophagy, apoptosis, redox signaling, and resistance to chemotherapeutic agents. Altogether, these studies support the role of miRNAs in the metabolic reprogramming hallmark of cancer cells and highlight their potential as predictive molecular markers of treatment response and/or targets that can be used for therapeutic intervention.

Growing data indicate that tumor progression and metastasis is dependent on the reprograming of cellular metabolism. Rapidly growing cancer cells undergo metabolic stress in a harsh microenvironment. AMP-activated protein kinase (AMPK) is an energy sensing factor that regulates bioenergetics and biosynthetic pathways within the cell, but its role under metastasis is in dispute. The best studied phenotype of cancer cells is aerobic glycolysis (the Warburg effect), an increased catabolism of glucose to lactate. However, glycolysis and mitochondrial oxidative phosphorylation may operate simultaneously in cancer cells. Many tumors may switch between these pathways accordingly to the current requirements. The alterations in metabolism of cancer cells combined with the overexpression of oncogenes (c-Myc) and transcription factors (Hypoxia-inducible factor 1a) confer a great advantage to malignant cells to avoid reactive oxygen species induced apoptosis. The determination of the role of AMPK network in metabolic reprogramming of metastatic cancer cells may help to identify the selective molecular targets for efficient anti-cancer therapies. In this review, we discuss the implications of AMPK activation in metabolic reprogramming of cancer cells and we present several potential therapeutic strategies targeting cancer cell metabolism. AMPK activator, biguanide metformin, either alone or in combination with other drugs, may selectively modulate signaling pathways, expresses the chemopreventive potential and can be used in current anti-cancer approaches. However, the ambiguous data suggest that the activation of AMPK may induce multiple effects and thus potential therapeutic anti-cancer approach should be carefully considered in relation to metabolic network of cancer cell signaling and other determinants such tumor stage and origin as well.

Tumor metabolism and metabolic reprogramming in cancer cells represent a promising area in oncology research, offering new avenues for therapeutic intervention. While the 'Warburg effect' highlights the reliance of many tumors on aerobic glycolysis, emerging evidence indicates that some cancers also depend on mitochondrial oxidative phosphorylation (OXPHOS) for energy production, cancer cell survival, tumor progression, metastasis, and drug resistance. We conducted a high-throughput, differential, phenotypic screening followed by a focused medicinal chemistry campaign, leading to the identification of novel, potent OXPHOS inhibitors. These lead compounds selectively target complex I of the mitochondrial electron transport chain, thereby disrupting ATP production and oxygen consumption in cancer cells. In-vitro studies in breast cancer cell lines, along with published data, suggest that MCT4 expression may serve as a biomarker for drug sensitivity. Notably, low MCT4 expression correlated with higher potency in cell growth assays. The identified compounds exhibited favorable drug-like properties, including good pharmacokinetics and oral bioavailability in mice. Daily oral dosing significantly inhibited tumor growth in two in-vivo breast cancer models with low MCT4 expression levels. This efficacy, however, was accompanied by body weight loss, indicating the need to enhance the therapeutic index through optimization or rational combination therapy strategies. These findings highlight the therapeutic potential of targeting mitochondrial OXPHOS in cancers with defined metabolic dependencies, offering a novel approach for exploiting tumor-specific metabolic vulnerabilities for improved cancer treatment.

Cancer cells face various metabolic challenges during tumor progression, including growth in the nutrient-altered and oxygen-deficient microenvironment of the primary site, intravasation into vessels where anchorage-independent growth is required, and colonization of distant organs where the environment is distinct from that of the primary site. Thus, cancer cells must reprogram their metabolic state in every step of cancer progression. Metabolic reprogramming is now recognized as a hallmark of cancer cells and supports cancer growth. Elucidating the underlying mechanisms of metabolic reprogramming in cancer cells may help identifying cancer targets and treatment strategies. This review summarizes our current understanding of metabolic reprogramming during cancer progression and metastasis, including cancer cell adaptation to the tumor microenvironment, defense against oxidative stress during anchorage-independent growth in vessels, and metabolic reprogramming during metastasis.

A detailed review on the role of miRNAs in mitochondrial-nuclear cross talk during cancer progression.

Studies of carcinogenic metabolism have shown that cancer cells have significant metabolic adaptability and that their metabolic dynamics undergo extensive reprogramming, which is a fundamental feature of cancer. The Warburg effect describes the preference of cancer cells for glycolysis over oxidative phosphorylation (OXPHOS), even under aerobic conditions. However, metabolic reprogramming in cancer cells involves not only glycolysis but also changes in lipid and amino acid metabolism. The mechanisms of these metabolic shifts are critical for the discovery of novel cancer therapeutic targets. Despite advances in the field of oncology, chemotherapy resistance, including multidrug resistance, remains a challenge. Research has revealed a correlation between metabolic reprogramming and anticancer drug resistance, but the underlying complex mechanisms are not fully understood. In addition, small extracellular vesicles (sEVs) may play a role in expanding metabolic reprogramming and promoting the development of drug resistance by mediating intercellular communication. The aim of this review is to assess the metabolic reprogramming processes that intersect with resistance to anticancer therapy, with particular attention given to the changes in glycolysis, lipid metabolism, and amino acid metabolism that accompany this phenomenon. In addition, the role of sEVs in disseminating metabolic reprogramming and promoting the development of drug-resistant phenotypes will be critically evaluated.