Melanoma Metabolism: Molecular Mechanisms and Therapeutic Implications in Cutaneous Oncology.

BACKGROUND: Melanoma, a highly aggressive skin cancer, is characterized by rapid progression and a high metastatic potential, presenting significant challenges in clinical oncology. A critical aspect of melanoma biology is its metabolic reprogramming, which supports tumor growth, survival, and therapeutic resistance. OBJECTIVE: This review aims to explore the key molecular mechanisms driving metabolic alterations in melanoma and their implications for developing therapeutic strategies. METHODS: A Pubmed search was conducted to analyze literature discussing key mechanisms of the Warburg effect, mitochondrial dysfunction, enhanced lipid metabolism, epigenetic modifications, and the tumor microenvironment. RESULTS: Metabolic reprogramming supports melanoma growth, proliferation, and survival. Understanding these complex metabolic dynamics provides valuable insights for developing targeted therapeutic strategies. CONCLUSION: Potential therapeutic interventions aimed at disrupting melanoma metabolism highlight the promise of precision medicine in improving treatment outcomes in cutaneous oncology. By targeting metabolic vulnerabilities, novel treatment approaches could significantly enhance the clinical management and prognosis of melanoma.

Histone H4K12 lactylation promotes malignancy progression in triple-negative breast cancer through SLFN5 downregulation.

Lactylation, a newly identified post-translational modification, is uncertain in its implication in triple-negative breast cancer (TNBC). In this study, we analyzed 60 TNBC samples using immunohistochemical staining and revealed elevated levels of pan-lactylated proteins and specific histone H4K12 lactylation in tumor tissues, correlating with TNBC progression. Lactate exposure in TNBC cell lines significantly induced lysine lactylation at the H4K12 site, leading to alterations in gene profiles and reduced apoptosis. These effects were attenuated by DCA or sodium Oxamate, inhibitors of endogenous lactate production. Gene sequencing showed an increase in Schlafen 5 (SLFN5) expression in TNBC cells treated with Oxamate, contrasting with the effects of lactate exposure. Analysis of TNBC tissues showed a negative correlation between H4K12 lactylation and SLFN5 protein levels. Overexpression of SLFN5 countered the effects of lactate on apoptosis and tumor growth, highlighting its pivotal role in TNBC malignancy. CUT&Tag sequencing indicated that lactylated H4K12 potentially binds to the SLFN5 promoter region. Luciferase reporter assays further verified that lactate-induced suppression of SLFN5 promoter activity is mediated by wild-type H4K12, but not by its R or A mutants, verified by both in vitro and in vivo apoptosis detection in response to lactate and Oxamate stimulation. These results establish that H4K12 lactylation, induced by lactate in TNBC cells, specifically suppresses SLFN5 expression, contributing to TNBC malignancy. Our findings illuminate a critical histone lactylation-dependent carcinogenic pathway in TNBC.

Role of glucose metabolic reprogramming in colorectal cancer progression and drug resistance.

Colorectal cancer (CRC), with the incidence and mortality rising on a yearly basis, greatly threatens people's health. It is considered an important hallmark of tumorigenesis that aberrant glucose metabolism in cancer cells, particularly the Warburg effect. In CRC, the Warburg effect predominantly influences cancer development and progression via its involvement in the glycolytic pathway regarding cell metabolism. The critical mechanisms underlying this process include key glycolytic enzymes, transport proteins, regulatory molecules, and signaling pathways. Furthermore, targeting the reprogrammed glucose metabolism in cancer cells can be potentially used for CRC treatment. However, the mechanisms driving CRC onset and progression, especially in relation to glucose metabolism reprogramming, are not fully understood and represent an emerging field of research. The review aims at providing new insights into the role that glucose metabolism reprogramming plays in the progression of CRC progression together with its resistance to treatment. Ultimately, these insights strive to diminish the risks of CRC metastasis and recurrence.

How Does Cancer Occur? How Should It Be Treated? Treatment from the Perspective of Alkalization Therapy Based on Science-Based Medicine.

This review article investigates the relationship between mitochondrial dysfunction and cancer progression, emphasizing the metabolic shifts that promote tumor growth. Mitochondria are crucial for cellular energy production, but they also play a significant role in cancer progression by promoting glycolysis even under oxygen-rich conditions, a phenomenon known as the Warburg effect. This metabolic reprogramming enables cancer cells to maintain an alkaline internal pH and an acidic external environment, which are critical for their proliferation and survival in hypoxic conditions. The article also explores the acidic tumor microenvironment (TME), a consequence of intensive glycolytic activity and proton production by cancer cells. This acidic milieu enhances the invasiveness and metastatic potential of cancer cells and contributes to increased resistance to chemotherapy. Alkalization therapy, which involves neutralizing this acidity through dietary modifications and the administration of alkalizing agents such as sodium bicarbonate, is highlighted as an effective strategy to counteract these adverse conditions and impede cancer progression. Integrating insights from science-based medicine, the review evaluates the effectiveness of alkalization therapy across various cancer types through clinical assessments. Science-based medicine, which utilizes inductive reasoning from observed clinical outcomes, lends support to the hypothesis of metabolic reprogramming in cancer treatment. By addressing both metabolic and environmental disruptions, this review suggests that considering cancer as primarily a metabolic disorder could lead to more targeted and effective treatment strategies, potentially improving outcomes for patients with advanced-stage cancers.

Development of a Competitive Nutrient-Based T-Cell Immunotherapy Designed to Block the Adaptive Warburg Effect in Acute Myeloid Leukemia.

Background: T-cell-based adoptive cell therapies have emerged at the forefront of cancer immunotherapies; however, failed long-term survival and inevitable exhaustion of transplanted T lymphocytes in vivo limits clinical efficacy. Leukemia blasts possess enhanced glycolysis (Warburg effect), exploiting their microenvironment to deprive nutrients (e.g., glucose) from T cells, leading to T-cell dysfunction and leukemia progression. Methods: Thus, we explored whether genetic reprogramming of T-cell metabolism could improve their survival and empower T cells with a competitive glucose-uptake advantage against blasts and inhibit their uncontrolled proliferation. Results: Here, we discovered that high-glucose concentration reduced the T-cell expression of glucose transporter GLUT1 (SLC2A1) and TFAM (mitochondrion transcription factor A), an essential transcriptional regulator of mitochondrial biogenesis, leading to their impaired expansion ex vivo. To overcome the glucose-induced genetic deficiency in metabolism, we engineered T cells with lentiviral overexpression of SLC2A1 and/or TFAM transgene. Multi-omics analyses revealed that metabolic reprogramming promoted T-cell proliferation by increasing IL-2 release and reducing exhaustion. Moreover, the engineered T cells competitively deprived glucose from allogenic blasts and lessened leukemia burden in vitro. Conclusions: Our findings propose a novel T-cell immunotherapy that utilizes a dual strategy of starving blasts and cytotoxicity for preventing uncontrolled leukemia proliferation.

Insights into Metabolic Reprogramming in Tumor Evolution and Therapy.

Background: Cancer remains a global health challenge, characterized not just by uncontrolled cell proliferation but also by the complex metabolic reprogramming that underlies its development and progression. Objectives: This review delves into the intricate relationship between cancer and its metabolic alterations, drawing an innovative comparison with the cosmological concepts of dark matter and dark energy to highlight the pivotal yet often overlooked role of metabolic reprogramming in tumor evolution. Methods: It scrutinizes the Warburg effect and other metabolic adaptations, such as shifts in lipid synthesis, amino acid turnover, and mitochondrial function, driven by mutations in key regulatory genes. Results: This review emphasizes the significance of targeting these metabolic pathways for therapeutic intervention, outlining the potential to disrupt cancer's energy supply and signaling mechanisms. It calls for an interdisciplinary research approach to fully understand and exploit the intricacies of cancer metabolism, pointing toward metabolic reprogramming as a promising frontier for developing more effective cancer treatments. Conclusion: By equating cancer's metabolic complexity with the enigmatic nature of dark matter and energy, this review underscores the critical need for innovative strategies in oncology, highlighting the importance of unveiling and targeting the "dark energy" within cancer cells to revolutionize future therapy and research.

Intratumoral Heterogeneity and Metabolic Cross-Feeding in a Three-Dimensional Breast Cancer Culture: An In Silico Perspective.

Today, the intratumoral composition is a relevant factor associated with the progression and aggression of cancer. Although it suggests a metabolic interdependence among the subpopulations inside the tumor, a detailed map of how this interdependence contributes to the malignant phenotype is still lacking. To address this issue, we developed a systems biology approach integrating single-cell RNASeq and genome-scale metabolic reconstruction to map the metabolic cross-feeding among the subpopulations previously identified in the spheroids of MCF7 breast cancer. By calibrating our model with expression profiles and the experimental growth rate, we concluded that the reverse Warburg effect emerges as a mechanism to optimize community growth. Furthermore, through an in silico analysis, we identified lactate, alpha-ketoglutarate, and some amino acids as key metabolites whose disponibility alters the growth rate of the spheroid. Altogether, this work provides a strategy for assessing how space and intratumoral heterogeneity influence the metabolic robustness of cancer, issues suggesting that computational strategies should move toward the design of optimized treatments.

Mitochondrial toxicity of selected natural compounds: in vitro assessment and in silico molecular docking and dynamics simulation.

Prangos uechtritzii Boiss & Hausskn stands out for its rich bioactive constituents including prantschimgin (PRA), imperatorin (IMP), suberosin (SUB), adicardin (ADI), and oxypeucedanin hydrate (OPH) in the Apiaceae family. Although these molecules contribute to several biological activities, their mitochondrial toxicity were not illuminated in depth with the appropriate in vitro and in silico models. Cell viability studies investigated the cytotoxic activities of molecules in HepG2 cells by replacing glucose with galactose due to Warburg effects. Mitochondrial toxicity (mitotoxicity) parameters such as cellular adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) levels were assessed with cytotoxic concentrations of selected molecules. Molecular docking and dynamics studies were also conducted against mitochondrial electron transport chain (ETC) complexes (I-V) with selected compounds. In vitro results showed that PRA, SUB, and IMP reduced cell viability more in galactose media compared to high glucose media in a dose-dependent manner. PRA, IMP, and SUB decreased ATP levels and MMP, especially in the galactose medium. The in silico study revealed that PRA, IMP, and SUB might bind to complexes I-V at different levels. The docking study demonstrated that PRA had the highest binding potential with the complexes, higher than the standard ligands in some cases. The molecular dynamics (MD) simulation study showed that PRA formed stable complexes with complexes II, III, and IV. In addition, PRA was anticipated to remain inside the binding site of complex II most stably during the 230 ns simulation period. Our study suggests that PRA, IMP, and SUB exhibit mitotoxicity.

Primary Retrovesical Leiomyosarcoma: A Case Report.

Soft tissue sarcomas (STS) are a rare group of malignant tumors in adults. This group of tumors contains a variety of subtypes, each with distinct clinical features and presentations. Leiomyosarcoma is among the most common subtypes, which typically occur within the uterus, retroperitoneum, abdomen, and large blood vessels. At presentation, tumors are often large and may have metastasized to the lungs, liver, or peritoneum. Given the rarity and variability of the disease, a multidisciplinary treatment approach is essential for management, however, further research is needed to develop histologic-specific guidelines and targeted treatments. Here, we present a case of a 69-year-old male who was found to have a large pelvic mass of unknown etiology after presenting to the emergency department with generalized weakness, decreased appetite, and an inability to ambulate. On examination, he was found to have testicular swelling and trace edema of bilateral lower extremities. Labs significant for lactic acidosis and CT chest/abdomen/pelvis showed a large heterogeneously enhancing mass within the pelvis measuring up to 15 cm x 12 cm x 15 cm, of uncertain origin, but highly concerning for malignancy. Biopsy with immunohistochemical stains of the mass revealed a grade 2 leiomyosarcoma. Due to the size and location of the mass, transfer to a tertiary care center was recommended. Computed tomography angiography (CTA) abdomen/pelvis and magnetic resonance imaging (MRI) abdomen/pelvis performed at the tertiary care hospital revealed a 16.6 cm heterogeneously enhancing, necrotic mass within the retrovesical pelvic space and three liver lesions, which were concerning for metastases. Due to the patient's deconditioning and poor functional status, surgical resection and radiation were not offered. The patient expired soon after his code status was changed to comfort care.

Diffuse Large B-cell Lymphoma with Severe Lactic Acidosis and Liver Failure: A Case Report and Literature Review.

Among causes of liver failure, liver failure due to lymphocytic infiltration is rare. Unlike typical liver failure, some cases present with severe lactic acidosis and a poor prognosis. We herein report a case of diffuse large B-cell lymphoma with severe lactic acidosis and liver failure. We further discuss the characteristics of similar cases in the literature, suggesting that intrahepatic infiltration by hematological malignant cells should be considered as a differential diagnosis in the presence of severe lactic acidosis and liver failure. This study underscores the importance of early recognition and serves as a reference for future cases.

Flavonoids as modulators of metabolic reprogramming in renal cell carcinoma (Review).

Renal cell carcinoma (RCC) is distinguished by its varied metabolic reprogramming driven by tumor suppressor gene dysregulation and oncogene activation. Tumors can adapt nutrient uptake and metabolism pathways to meet the altered biosynthetic, bioenergetic and redox demands of cancer cells, whereas conventional chemotherapeutics and molecular inhibitors predominantly target individual metabolic pathways without addressing this adaptability. Flavonoids, which are well­known for their antioxidant and anti­inflammatory properties, offer a unique approach by influencing multiple metabolic targets. The present comprehensive review reveals the intricate processes of RCC metabolic reprogramming, encompassing glycolysis, mitochondrial oxidative phosphorylation and fatty acid biosynthesis. The insights derived from the present review may contribute to the understanding of the specific anticancer mechanisms of flavonoids, potentially paving the way for the development of natural antitumor drugs focused on the metabolic reprogramming of RCC.

A narrative review: exploring viral-induced malignancies through the lens of dysregulated cellular metabolism and glucose transporters.

INTRODUCTION: In this narrative review, we unravel the complex interplay between oncogenic viruses, cellular metabolism, and glucose transporter (GLUT) dysregulation in viral-induced malignancies. METHODS: By explaining the diverse mechanisms through which seven major oncoviruses manipulate metabolic pathways and GLUT expression, particularly GLUT1, we provide novel insights into the critical role of metabolic reprogramming in viral replication and oncogenesis. RESULTS: Our exploration of the molecular pathways targeted by viral oncoproteins reveals a similarity between the metabolic alterations induced by viral infections and those observed in neoplastic transformation. A key finding of our review is the overexpression of GLUTs, particularly GLUT1, as a hallmark of both viral infections and many cancers. CONCLUSIONS: By elucidating the complex interplay between viral oncoproteins, oncogene activation, tumor suppressor gene loss, and GLUT overexpression, we highlight the potential of GLUTs as novel targets for diagnosis, prognosis, and therapy of viral-induced malignancies.

Harnessing glucose metabolism with nanomedicine for cancer treatment.

The significance of metabolic processes in cancer biology has garnered substantial attention, as they are essential for meeting the anabolic demands and maintaining the redox balance of rapidly dividing cancer cells. A distinctive feature of tumors is that cancer cells, unlike normal cells, exhibit an increased rate of glucose metabolism. They predominantly relying on aerobic glycolysis to metabolize glucose, which enables these cells to supply energy and produce the necessary building blocks for growth. Targeting glucose metabolism has led to the development of various cancer treatments. However, these agents often have limited efficacy due to factors such as poor stability and solubility, rapid clearance and an insufficient amount of the drug reaching the target site. These limitations can be overcome by preparing nano dosage forms through nanotechnology, which leverages the unique properties of nanomaterials to deliver drugs more precisely to target tissues with controlled release. In this review, we provide a comprehensive overview of the latest advancements in nanomedicine, focusing on the modulation of glucose metabolism in cancer cells. We discuss the design and application of various strategies that have been engineered to target the metabolic hallmarks of cancer. These nanomedicine strategies aim to exploit the metabolic vulnerabilities of cancer cells, thereby offering novel approaches to cancer therapy. The review highlights the innovative nanomaterials and their potential to deliver therapeutic agents more effectively, as well as the challenges and considerations in translating these nanomedicines from bench to bedside. By targeting the glucose metabolism of cancer cells, these nanoscale interventions hold promise for improving treatment outcomes and potentially overcoming the resistance that often plagues conventional cancer therapies.

In Vitro Methylene Blue and Carboplatin Combination Triggers Ovarian Cancer Cells Death.

Ovarian cancer presents a dire prognosis and high mortality rates, necessitating the exploration of alternative therapeutic avenues, particularly in the face of platinum-based chemotherapy resistance. Conventional treatments often overlook the metabolic implications of cancer, but recent research has highlighted the pivotal role of mitochondria in cancer pathogenesis and drug resistance. This study delves into the metabolic landscape of ovarian cancer treatment, focusing on modulating mitochondrial activity using methylene blue (MB). Investigating two epithelial ovarian cancer (EOC) cell lines, OV1369-R2 and OV1946, exhibiting disparate responses to carboplatin, we sought to identify metabolic nodes, especially those linked to mitochondrial dysfunction, contributing to chemo-resistance. Utilizing ARPE-19, a normal retinal epithelial cell line, as a control model, our study reveals MB's distinct cellular uptake, with ARPE-19 absorbing 5 to 7 times more MB than OV1946 and OV1369-R2. Treatment with 50 µM MB (MB-50) effectively curtailed the proliferation of both ovarian cancer cell lines. Furthermore, MB-50 exhibited the ability to quell glutaminolysis and the Warburg effect in cancer cell cultures. Regarding mitochondrial energetics, MB-50 spurred oxygen consumption, disrupted glycolytic pathways, and induced ATP depletion in the chemo-sensitive OV1946 cell line. These findings highlight the potential of long-term MB exposure as a strategy to improve the chemotherapeutic response in ovarian cancer cells. The ability of MB to stimulate oxygen consumption and enhance mitochondrial activity positions it as a promising candidate for ovarian cancer therapy, shedding light on the metabolic pressures exerted on mitochondria and their modulation by MB, thus contributing to a deeper understanding of mitochondrial dysregulation and the metabolic underpinnings of cancer cell proliferation.

Hippocampal PDHA1 gene knockout inhibits the Warburg effect leading to cognitive dysfunction and attenuates the beneficial effects of ZiBuPiYin recipe on cognition.

ETHNOPHARMACOLOGICAL RELEVANCE: The attenuation of the Warburg effect is an important pathological feature of cognitive dysfunction, and enhancing the Warburg effect is conducive to improving cognitive function. However, the pathogenic mechanisms underlying cognitive dysfunction remain incompletely elucidated. ZiBuPiYin Recipe (ZBPYR) is a traditional Chinese herbal compound used clinically for the treatment of cognitive dysfunction with significant efficacy. Nonetheless, the molecular mechanism underlying its beneficial effects remains elusive. AIM OF THE STUDY: The objective of this study is to investigate whether the attenuation of the Warburg effect exists in a mouse model of cognitive dysfunction induced by knockout of the pyruvate dehydrogenase E1 component subunit alpha (PDHA1) gene in the hippocampus, as well as the interventional effect of ZBPYR. MATERIALS AND METHODS: Using mice with PDHA1 gene knockout in the hippocampus and their littermate control mice as study subjects, behavioral experiments were conducted to assess the impact of PDHA1 gene knockout on cognitive function and the interventional effect of ZBPYR. We detected the expression of the Warburg effect-associated rate-limiting enzymes and PI3K/AKT pathway-related proteins. Subsequently, in PC12 cells, we explored the effect of the Warburg effect on cell apoptosis as well as the role of PDHA1 in the regulation of the PI3K/AKT-Warburg effect and the potential mechanism of ZBPYR in improving cognitive function. RESULTS: Mice with knockout of the PDHA1 gene in the hippocampus exhibited cognitive dysfunction, inhibition of the PI3K/AKT pathway, reduction of the Warburg effect, and neuronal damage. In vitro experiments indicated that silencing of PDHA1 in the hippocampus inhibited the PI3K/AKT-Warburg effect, leading to cell apoptosis and mediated the effect of ZBPYR in improving cognitive function. CONCLUSION: Our data not only suggest that the hippocampal PDHA1-PI3K/AKT-Warburg effect may be involved in the pathogenesis of cognitive dysfunction, but also demonstrate that PDHA1 knockout can abolish the beneficial effects of ZBPYR on cognition. This research aids in unraveling the cause of cognitive dysfunction and, therefore, offers a promising and innovative therapeutic target for these patients.

Terpenoids: Unlocking Their Potential on Cancer Glucose Metabolism.

Cancer incidence has increased globally and has become the leading cause of death in the majority of countries. Many cancers have altered energy metabolism pathways, such as increased glucose uptake and glycolysis, as well as decreased oxidative phosphorylation. This is known as the Warburg effect, where cancer cells become more reliant on glucose to generate energy and produce lactate as an end product, even when oxygen is present. These are attributed to the overexpression of key glycolytic enzymes, glucose transporters, and related signaling pathways that occur in cancer cells. Therefore, overcoming metabolic alterations in cancer cells has recently become a target for therapeutic approaches. Natural products have played a key role in drug discovery, especially for cancer and infectious diseases. In this review, we are going to focus on terpenoids, which are gradually gaining popularity among drug researchers due to their reported anti-cancer effects via cell cycle arrest, induction of apoptosis, reduction of proliferation, and metastasis. This review summarizes the potential of 13 terpenoid compounds as anti-glycolytic inhibitors in different cancer models, primarily by inhibiting the glucose uptake and the generation of lactate, as well as by downregulating enzymes associated to glycolysis. As a conclusion, disruption of cancer cell glycolysis may be responsible for the anti-cancer activity of terpenoids.

Metabolic Reprogramming in Glioblastoma Multiforme: A Review of Pathways and Therapeutic Targets.

Glioblastoma (GBM) is an aggressive and highly malignant primary brain tumor characterized by rapid growth and a poor prognosis for patients. Despite advancements in treatment, the median survival time for GBM patients remains low. One of the crucial challenges in understanding and treating GBMs involves its remarkable cellular heterogeneity and adaptability. Central to the survival and proliferation of GBM cells is their ability to undergo metabolic reprogramming. Metabolic reprogramming is a process that allows cancer cells to alter their metabolism to meet the increased demands of rapid growth and to survive in the often oxygen- and nutrient-deficient tumor microenvironment. These changes in metabolism include the Warburg effect, alterations in several key metabolic pathways including glutamine metabolism, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, increased uptake and utilization of glutamine, and more. Despite the complexity and adaptability of GBM metabolism, a deeper understanding of its metabolic reprogramming offers hope for developing more effective therapeutic interventions against GBMs.

SELENBP1 Inhibits the Warburg Effect and Tumor Growth by Reducing the HIF1α Expression in Colorectal Cancer.

INTRODUCTION: Colorectal cancer (CRC) is experiencing a significant increase in both incidence and mortality rates globally. The expression of Selenium-binding protein 1 (SELENBP1) has been reported to be notably downregulated in various malignancies, yet its biological functions and cellular mechanisms in CRC remain incompletely understood. METHOD: In our investigation, we observed the downregulation of SELENBP1 in CRC tissues through quantitative real-time PCR and western blotting and identified a positive correlation between higher SELENBP1 expression and improved survival prognosis using Kaplan-Meier survival analysis. Through loss-of-function and gain-of-function studies, we demonstrated the tumor-suppressive roles of SELENBP1 in CRC, supported by results from both in vitro and in vivo experiments. Furthermore, we uncovered the pivotal functions of SELENBP1 in suppressing aerobic glycolysis in CRC cells by regulating glucose uptake, lactate generation, and extracellular acidification rate. RESULT: At a mechanistic level, we found that SELENBP1 inhibits the expression of the key glycolytic modulator hypoxia-inducible factor 1 subunit alpha (HIF1α), and the inhibition of glycolysis by SELENBP1 can be reversed by ectopic expression of HIF1α. Therefore, our study highlights the potential of SELENBP1 as a promising target for CRC therapy, given its significant impact on tumor suppression and reprogrammed glucose metabolism. CONCLUSION: These findings contribute to a deeper understanding of the molecular mechanisms underlying CRC progression and may pave the way for the development of targeted therapies for this challenging disease.

Glucose metabolism in glioma: an emerging sight with ncRNAs.

Glioma is a primary brain tumor that grows quickly, has an unfavorable prognosis, and can spread intracerebrally. Glioma cells rely on glucose as the major energy source, and glycolysis plays a critical role in tumorigenesis and progression. Substrate utilization shifts throughout glioma progression to facilitate energy generation and biomass accumulation. This metabolic reprogramming promotes glioma cell proliferation and metastasis and ultimately decreases the efficacy of conventional treatments. Non-coding RNAs (ncRNAs) are involved in several glucose metabolism pathways during tumor initiation and progression. These RNAs influence cell viability and glucose metabolism by modulating the expression of key genes of the glycolytic pathway. They can directly or indirectly affect glycolysis in glioma cells by influencing the transcription and post-transcriptional regulation of oncogenes and suppressor genes. In this review, we discussed the role of ncRNAs in the metabolic reprogramming of glioma cells and tumor microenvironments and their abnormal expression in the glucometabolic pathway in glioma. In addition, we consolidated the existing theoretical knowledge to facilitate the use of this emerging class of biomarkers as biological indicators and potential therapeutic targets for glioma.

Unraveling the Mystery of Energy-Sensing Enzymes and Signaling Pathways in Tumorigenesis and Their Potential as Therapeutic Targets for Cancer.

Cancer research has advanced tremendously with the identification of causative genes, proteins, and signaling pathways. Numerous antitumor drugs have been designed and screened for cancer therapeutics; however, designing target-specific drugs for malignant cells with minimal side effects is challenging. Recently, energy-sensing- and homeostasis-associated molecules and signaling pathways playing a role in proliferation, apoptosis, autophagy, and angiogenesis have received increasing attention. Energy-metabolism-based studies have shown the contribution of energetics to cancer development, where tumor cells show increased glycolytic activity and decreased oxidative phosphorylation (the Warburg effect) in order to obtain the required additional energy for rapid division. The role of energy homeostasis in the survival of normal as well as malignant cells is critical; therefore, fuel intake and expenditure must be balanced within acceptable limits. Thus, energy-sensing enzymes detecting the disruption of glycolysis, AMP, ATP, or GTP levels are promising anticancer therapeutic targets. Here, we review the common energy mediators and energy sensors and their metabolic properties, mechanisms, and associated signaling pathways involved in carcinogenesis, and explore the possibility of identifying drugs for inhibiting the energy metabolism of tumor cells. Furthermore, to corroborate our hypothesis, we performed meta-analysis based on transcriptomic profiling to search for energy-associated biomarkers and canonical pathways.