While NDUFAF6 is implicated in breast cancer, its specific role remains unclear.

The expression levels and prognostic significance of NDUFAF6 in breast cancer were assessed using The Cancer Genome Atlas, Gene Expression Omnibus, Kaplan-Meier plotter and cBio-Portal databases. We knocked down NDUFAF6 in breast cancer cells using small interfering RNA and investigated its effects on cell proliferation and migration ability. We performed gene expression analysis and validated key findings using protein analysis. We also assessed mitochondrial activity and cellular metabolism.

NDUFAF6 was highly expressed in breast cancer, which was associated with a poorer prognosis. Knockdown of NDUFAF6 reduced the proliferation and migration ability of breast cancer cells. Transcriptome analysis revealed 2,101 differentially expressed genes enriched in apoptosis and mitochondrial signaling pathways. Western blot results showed NDUFAF6 knockdown enhanced apoptosis. In addition, differential gene enrichment analysis was related to mitochondrial signaling pathways, and western blot results verified that mitophagy was enhanced in NDUFAF6 knockdown breast cancer cells. JC-1 assay also showed that mitochondrial dysfunction and reactive oxygen species content were increased after knocking down NDUFAF6. In addition, basal and maximal mitochondrial oxygen consumption decreased, and intracellular glycogen content increased.

Knockdown of NDUFAF6 resulted in apoptosis and mitophagy in breast cancer cells and NDUFAF6 may be a potential molecular target for breast cancer therapy.

Mitochondria represent a fundamental structure for cellular homeostasis, controlling multiple conditions regarding energetic functions and cellular survival. To maintain these organelles functioning in ideal conditions, their membranes count with ion channels for different inorganic ions, which must be balanced to offer the proper function for both the organelle and the cell. However, studies have shown that other health conditions impair the activities of mitochondrial ion channels, including cancer. In this sense, the altered activities of potassium, calcium, and calcium-activated potassium channels are mainly linked with cancer development and cellular homeostasis alteration, demonstrating their role as pharmacological targets. With that in mind, scientists have found significant mitochondrial and cellular responses related to apoptosis and reduction of cellular survival from cells with modulated ion channels, indicating the potential of this possible therapy in carcinogenic contexts. Nonetheless, few studies still evaluate mitochondrial ion channel modulation as a treatment against cancer. Hence, more research must be conducted on this subject.

The dissemination of malignant cells to the brain is a late-stage complication of cancer, leading to significant morbidity and mortality. Brain metastases (BM) affect 20-30% of cancer patients, primarily originating from lung cancer, breast cancer, and melanoma. Despite advances in molecular-targeted therapies, brain metastatic disease remains incurable, with a poor median survival of ≤12 months if left untreated. The lack of therapeutic efficacy is mainly attributed to the presence of the blood-brain barrier (BBB) and genetic differences between BM and their primary tumors. Previously published data have identified potential driver mutations of BM. However, the mechanisms underlying brain cancer dissemination remain unknown. Recent studies emphasize the pivotal role of metabolic adaptations in supporting the metastatic process, particularly in the nutrient-poor microenvironment characteristic of the brain. Understanding the interplay between metabolism and genetic alterations associated with brain metastatic disease could unveil novel therapeutic targets that are more effective in treating patients. This review focuses on relevant metabolic pathways in cancer, particularly brain cancer dissemination, while also presenting information on current preclinical models of BM, relevant clinical trials, and preclinical studies targeting metabolic reprogramming, providing an overview for advancing therapeutic strategies in BM.

Glioblastoma Multiforme (GBM) is a highly malignant and diffusely invasive WHO Grade IV brain tumor arising from glial and neural stem cells. GBM is characterized by rapid proliferation and migration, aggressive invasion of local brain parenchyma, a hypoxic microenvironment, resistance to apoptosis and high vascular remodeling and angiogenesis. These hallmarks contribute to a near universal tumor recurrence after treatment or resection and poor patient prognosis. Ion channels, a superfamily of proteins responsible for permitting ion flux across otherwise impermeant membranes, show extensive remodeling in GBM with aberrant function mechanistically linked to manipulation of each of these hallmarks. In this review, we will discuss the known links between ion channel expression and activity and cellular processes that are enhanced or perturbed during GBM formation or progression. We will also discuss the extent to which basic or translational findings on ion channels in GBM samples or cell lines have shown preclinical promise towards the development of improved therapeutics against GBMs.

Head and neck cancer (HNC) is a common disease in otorhinolaryngology. Its prevalence is higher in men than in women and is mostly related to tobacco, alcohol and viral infections. Despite significant advances in the treatment of HNC in recent years, the mortality rate is still high and most patients are diagnosed at an advanced stage, and the prognosis for these patients is even worse. Earlier metastasis makes the treatment of HNC trickier. Therefore, actively seeking ways to treat HNC more effectively has been the goal of head and neck surgeons. Potassium (K+) channels are the most diverse ion channels found in all areas of life. Voltage-gated potassium (Kv) channels are the most important subfamily of K+ channels. Multiple Kv channels are associated with the development of HNC. This review focuses on several Kv channels associated with HNC.

Marred by a median survival of only around 12-15 months coupled with poor prognosis and effective therapeutic deprived drug armory, treatment/management of glioblastoma has proved to be a daunting task. Surgical resection, flanked by radiotherapy and chemotherapy with temozolomide, stands as the standard of care; however, this trimodal therapy often manifests limited efficacy due to the heterogeneous and highly infiltrative nature of GBM cells. In addition, the existence of the blood-brain barrier, tumor microenvironment, and the immunosuppressive nature of GBM, along with the encountered resistance of GBM cells towards conventional therapy, also hinders the therapeutic applications of chemotherapeutics in GBM. This review presents key insights into the molecular pathology of GBM, including genetic mutations, signaling pathways, and tumor microenvironment characteristics. Recent innovations such as immunotherapy, oncolytic viral therapies, vaccines, nanotechnology, electric field, and cancer neuroscience, as well as their clinical progress, have been covered. In addition, this compilation also encompasses a discussion on the role of personalized medicine in tailoring treatments based on individual tumor profiles, an approach that is gradually shifting the paradigm in GBM management. Endowed with the learnings imbibed from past failures coupled with the zeal to embrace novel/multidisciplinary approaches, researchers appear to be on the right track to pinpoint more effective and durable solutions in the context of GBM treatment.

Endometriosis affects about 10 % of women of reproductive age, leading to a disabling gynecologic condition. Chronic pain, inflammation, and oxidative stress have been identified as the molecular pathways involved in the progression of this disease, although its precise etiology remains uncertain. Although mitochondria are considered crucial organelles for cellular activity, their dysfunction has been linked to the development of this disease. The purpose of this review is to examine the functioning of the mitochondrion in endometriosis: in particular, we focused on the mitochondrial dynamics of biogenesis, fusion, and fission. Since excessive mitochondrial activity is reported to affect cell proliferation, we also considered mitophagy as a mechanism involved in limiting disease development. To better understand mitochondrial activity, we also considered alterations in circadian rhythms, the gut microbiome, and estrogen receptors: indeed, these mechanisms are also involved in the development of endometriosis. In addition, we focused on recent research about the impact of numerous substances on mitochondrial activity; some of them may offer a future breakthrough in endometriosis treatment by acting on mitochondria and inhibiting cell proliferation.

In this study, we have screened out an effective triphenylphosphine-derived initiator (2-TMOPP) for efficient ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCA ROP) and demonstrated the potential of the prepared helical polypeptide as an efficient ion channel. By optimizing polymerization conditions, 2-TMOPP exhibited precise control over the molecular weight and polydispersity index for the prepared polypeptides, the universality for different NCA monomers, and the ability to form α-helical secondary structures. By further incorporating ion binding groups and regulating the molecular length, α-helical polypeptide PLCE was capable of inserting into lipid bilayers and possessing the function of ion transport (H+/K+ antiport) via a channel mechanism (EC50 = 12.75 ± 1.58 μg mL-1). PLCE also showed anticancer activity toward HeLa cells, with an IC50 value of approximately 69.67 ± 1.20 μg mL-1 after 20 h coculture, showing the possibility for future practical application in biomedical fields.

Brain metastases (BMs) are the most common intracranial tumors in adults and the major cause of cancer-related morbidity and mortality. The occurrence of BMs varies according to the type of primary tumors with most frequence in lung cancer, melanoma and breast cancer. Among of them, lung cancer has been reported to have a higher risk of BMs than other types of cancers with 40 ~ 50% of such patients will develop BMs during the course of disease. BMs lead to many neurological complications and result in a poor quality of life and short life span. Although the treatment strategies were improved for brain tumors in the past decades, the prognosis of BMs patients is grim. Poorly understanding of the molecular and cellular characteristics of BMs and the complicated interaction with brain microenvironment are the major reasons for the dismal prognosis of BM patients. Recent studies have enhanced understanding of the mechanisms of BMs. The newly identified potential therapeutic targets and the advanced therapeutic strategies have brought light for a better cure of BMs. In this review, we summarized the mechanisms of BMs during the metastatic course, the molecular and cellular landscapes of BMs, and the advances of novel drug delivery systems for overcoming the obstruction of blood-brain barrier (BBB). We further discussed the challenges of the emerging therapeutic strategies, such as synergistic approach of combining targeted therapy with immunotherapy, which will provide vital clues for realizing the precise and personalized medicine for BM patients in the future.

Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings, particularly in intricate conditions such as cancer. Specifically, lactate has been demonstrated to be pivotal in molding the tumor microenvironment (TME) through its effects on different cell populations. Within tumor cells, lactate impacts cell signaling pathways, augments the lactate shuttle process, boosts resistance to oxidative stress, and contributes to lactylation. In various cellular populations, the interplay between lactate and immune cells governs processes such as cell differentiation, immune response, immune surveillance, and treatment effectiveness. Furthermore, communication between lactate and stromal/endothelial cells supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, and drug resistance. Focusing on lactate production and transport, specifically through lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT), has shown promise in the treatment of cancer. Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy, leading to a synergistic therapeutic effect when combined with immunotherapy. The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism, highlighting the Heel of Achilles for cancer treatment.

Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.

Chloroquine (CQ), an autophagy antagonist, has been recently explored as a repurposable medicine for cancer; however the exact mechanism of its action is still not known. The present study investigated the effect of CQ on colorectal cancer cells to elucidate the underlying molecular mechanisms. We report for the first time that CQ suppresses hypoxia-induced growth and survival of HCT-116 cells by reducing glycolytic capacity and NAD+ production through inhibition of PDK1. Furthermore, in silico and in vitro studies revealed that CQ induces structural alteration in the PDK1 protein, leading to its destabilization and promotes its enhanced degradation by proteases. This degradation is in turn inhibited by the MG-132 protease inhibitor. Moreover, CQ-induced suppression of PDK1 results in mitochondrial damage through excessive production of ROS, as reflected by the reduction in mitochondrial membrane potential, which in turn triggers apoptosis through PARP cleavage and Caspase activation. These findings advocate CQ as a promising repurposable chemotherapeutic for colorectal cancer and a novel inhibitor of PDK1.

Complex multicellular organisms are composed of distinct tissues involving specialized cells that can perform specific functions, making such life forms possible. Species are defined by their genomes, and differences between individuals within a given species directly result from variations in their genetic codes. While genetic alterations can give rise to disease-causing acquisitions of distinct cell identities, it is now well-established that biochemical imbalances within a cell can also lead to cellular dysfunction and diseases. Specifically, nongenetic chemical events orchestrate cell metabolism and transcriptional programs that govern functional cell identity. Thus, imbalances in cell signaling, which broadly defines the conversion of extracellular signals into intracellular biochemical changes, can also contribute to the acquisition of diseased cell states. Metal ions exhibit unique chemical properties that can be exploited by the cell. For instance, metal ions maintain the ionic balance within the cell, coordinate amino acid residues or nucleobases altering folding and function of biomolecules, or directly catalyze specific chemical reactions. Thus, metals are essential cell signaling effectors in normal physiology and disease. Deciphering metal ion signaling is a challenging endeavor that can illuminate pathways to be targeted for therapeutic intervention. Here, we review key cellular processes where metal ions play essential roles and describe how targeting metal ion signaling pathways has been instrumental to dissecting the biochemistry of the cell and how this has led to the development of effective therapeutic strategies.

From a cancer-centric perspective, radiotherapy has been primarily viewed as a localised treatment modality, targeting cancer tissues with ionising radiation to induce DNA damage and cell death [...].

Potassium ion (K+) is the most abundant metal ion in cells and plays an indispensable role in practically all biological systems. Although there have been reports of both synthetic and genetically encoded fluorescent K+ indicators, there remains a need for an indicator that is genetically targetable, has high specificity for K+ versus Na+, and has a high fluorescent response in the red to far-red wavelength range. Here, we introduce a series of chemigenetic K+ indicators, designated as the HaloKbp1 series, based on the bacterial K+-binding protein (Kbp) inserted into HaloTag7 self-labeled with environmentally sensitive rhodamine derivatives. This series of high-performance indicators features high brightness in the red to far-red region, large intensiometric fluorescence changes, and a range of Kd values. We demonstrate that they are suitable for the detection of physiologically relevant K+ concentration changes such as those that result from the Ca2+-dependent activation of the BK potassium channel.

Patients with brain tumors suffer from intense psychosocial distress. Although the prevalence of depressive symptoms in patients with brain tumors is high, the pharmacological antidepressant treatment of those patients is not well defined and results from clinical trials are largely missing. In this review, we describe the current standard of evidence and clinical guidelines for the pharmacological treatment of depression in brain tumor patients. We present specific side effects and interactions that should guide treatment decisions. Furthermore, we provide evidence for the diagnosis, screening and risk factors for depression in brain tumor patients and we elaborate on potential antineoplastic effects of antidepressant drugs and ongoing clinical trials. Antidepressant drugs should not be withheld from patients with brain tumors. Future clinical trials should explore the effectiveness and side effects of antidepressants in this specific patient population.

Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.

Different anesthetics exert different effects on the long-term outcomes of various cancers. The TWIK-related acid sensitive potassium 3 (TASK-3) channel is an important target of anesthetics and is upregulated in various cancers. However, the role and underlying mechanism of TASK-3 channel in the effects of anesthetics on ovarian cancer remain unknown. Here, we tested whether the TASK-3 channel contributes to the effects of anesthetics on ovarian cancers. We found that the TASK-3 channel was overexpressed in human ovarian cancer and ovarian cancer cell lines. Clinically relevant concentrations of lidocaine, as a TASK-3 channel inhibitor, exert inhibitory effects on tumor growth and metastasis of ovarian cancer cells in vitro and in vivo, whereas the TASK-3 channel potent activator sevoflurane had protumor effects and propofol had no significant effects on tumor growth and metastasis of ovarian cancer. Knockdown of the TASK-3 channel by TASK-3 shRNA attenuated the effects of lidocaine and sevoflurane. Moreover, mitochondrial TASK-3 channel contributes to the effects of lidocaine and sevoflurane on the mitochondrial functions of ovarian cancer. Taken together, the TASK-3 channel, especially the mitochondrial TASK-3 (MitoTASK-3) channel, is a molecular substrate for the effects of lidocaine and sevoflurane on the tumor growth and metastasis of ovarian cancer.

This study summarizes and analyzes the relationship between mitochondria and the pathogenesis of lung cancer. The related articles in the Web of Science core literature database are searched and collected, and the data are processed by R software, Citespace, VOSviewer, and Excel. A total of 4476 related papers were retrieved, 4476 articles from 20162 co-authors of 3968 institutions in 84 countries and published in 951 journals. Through various bibliometric analysis tools, the relationship between mitochondria and the pathogenesis of lung cancer was analyzed, the previous research results were summarized, and the potential research direction was found.

Perfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that have attracted considerable attention due to their widespread utilization, resilient characteristics, adverse health implications, and regulatory scrutiny. Despite documented toxicity in living organisms, the precise molecular mechanisms governing the induced adverse effects remain unclear. This study aims to elucidate mechanisms of toxic action by collecting empirical data sets along oxidative stress and metabolic disruption pathways. We investigated the impact of long-chain PFAS (perfluorooctanoic acid (PFOA)) and its short-chain analog (perfluorobutanoic acid (PFBA)) on human neuronal cells (SH-SY5Y). The functionalities of enzymes associated with oxidative stress (catalase and glutathione reductase) and cellular metabolism (lactate dehydrogenase and pyruvate dehydrogenase) were also characterized. Our results reveal that a 24-hour exposure to PFOA and PFBA generated significant levels of reactive oxygen species. Correspondingly, there was a notable decline in catalase and glutathione reductase activities, with PFBA demonstrating a more pronounced effect. High concentrations of PFOA and PFBA reduced metabolic activity. Lactate dehydrogenase activity was only impacted by a high concentration of PFBA, while pyruvate dehydrogenase activity was decreased with PFBA exposure and increased with PFOA exposure. The findings from this study contribute to the knowledge of PFAS and cell interactions and reveal the potential underlying mechanisms of PFAS-induced toxicity.

Bioenergetic remodeling of core energy metabolism is essential to the initiation, survival, and progression of cancer cells through exergonic supply of adenosine triphosphate (ATP) and metabolic intermediates, as well as control of redox homeostasis. Mitochondria are evolutionarily conserved organelles that mediate cell survival by conferring energetic plasticity and adaptive potential. Mitochondrial ATP synthesis is coupled to the oxidation of a variety of substrates generated through diverse metabolic pathways. As such, inhibition of the mitochondrial bioenergetic system by restricting metabolite availability, direct inhibition of the respiratory Complexes, altering organelle structure, or coupling efficiency may restrict carcinogenic potential and cancer progression.

Here, we review the role of bioenergetics as the principal conductor of energetic functions and carcinogenesis while highlighting the therapeutic potential of targeting mitochondrial functions.

Mitochondrial bioenergetics significantly contribute to cancer initiation and survival. As a result, therapies designed to limit oxidative efficiency may reduce tumor burden and enhance the efficacy of currently available antineoplastic agents.

The stability of the human telomere G-quadruplex (G4) is directly linked to cancer disease. The human telomere is mostly associated with the flanking nucleobases, which can affect the stability of G4. Hence, in this study, the effect of the flanking nucleobases in the context of their chemical nature, number, and position on the structure and stability of G4 has been investigated in varying concentrations of KCl mimicking the normal and cancer KCl microenvironments. The addition of flanking nucleobases does not alter the G4 topology. However, the presence of merely a single flanking nucleobase destabilizes the telomeric G4. This destabilizing effect is more prominent for thymine than adenine flanking nucleobase, probably due to the formation of the intermolecular G4 topology by thymine. Interestingly, the change in the stability of the telomeric G4 in the presence of thymine flanking nucleobase is sensitive to the concentration of KCl relevant to the normal and cancerous microenvironments, in contrast to adenine. Flanking nucleobases have a greater impact at the 5' end compared to the 3' end, particularly noticeable in KCl concentrations resembling the normal microenvironment rather than the cancerous one. These findings indicate that the effect of the flanking nucleobases on telomeric G4 is different in the KCl salt relevant to normal and cancerous microenvironments. This study may be helpful in attaining molecular-level insight into the role of G4 in telomeric length regulation under normal and cancerous KCl salt conditions.

Skeletal muscle is heterogeneous tissue, composed of fast-twitch fibers primarily relying on glycolysis and slow-twitch fibers primarily relying on oxidative phosphorylation. The relative expression and balance of glycolysis and oxidative phosphorylation in skeletal muscle are crucial for muscle growth and skeletal muscle metabolism. Here, we employed multi-omics approaches including transcriptomics, proteomics, phosphoproteomics, and metabolomics to unravel the role of circMYLK4, a differentially expressed circRNA in fast and slow-twitch muscle fibers, in muscle fiber metabolism. We discovered that circMYLK4 inhibits glycolysis and promotes mitochondrial oxidative phosphorylation. Mechanistically, circMYLK4 interacts with the voltage-gated calcium channel auxiliary subunit CACNA2D2, leading to the inhibition of Ca2+ release from the sarcoplasmic reticulum. The decrease in cytoplasmic Ca2+ concentration inhibits the expression of key enzymes, PHKB and PHKG1, involved in glycogen breakdown, thereby suppressing glycolysis. On the other hand, the increased fatty acid β-oxidation enhances the tricarboxylic acid cycle and mitochondrial oxidative phosphorylation. In general, circMYLK4 plays an indispensable role in maintaining the metabolic homeostasis of skeletal muscle.

Rarely has a chemical elicited as much controversy as dichloroacetate (DCA). DCA was initially considered a dangerous toxic industrial waste product, then a potential treatment for lactic acidosis. However, the main controversies started in 2008 when DCA was found to have anti-cancer effects on experimental animals. These publications showed contradictory results in vivo and in vitro such that a thorough consideration of this compound's in cancer is merited. Despite 50 years of experimentation, DCA's future in therapeutics is uncertain. Without adequate clinical trials and health authorities' approval, DCA has been introduced in off-label cancer treatments in alternative medicine clinics in Canada, Germany, and other European countries. The lack of well-planned clinical trials and its use by people without medical training has discouraged consideration by the scientific community. There are few thorough clinical studies of DCA, and many publications are individual case reports. Case reports of DCA's benefits against cancer have been increasing recently. Furthermore, it has been shown that DCA synergizes with conventional treatments and other repurposable drugs. Beyond the classic DCA target, pyruvate dehydrogenase kinase, new target molecules have also been recently discovered. These findings have renewed interest in DCA. This paper explores whether existing evidence justifies further research on DCA for cancer treatment and it explores the role DCA may play in it.

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.

The xanthone dimer 12-O-deacetyl-phomoxanthone A (12-ODPXA) was extracted from the secondary metabolites of the endophytic fungus Diaporthe goulteri. The 12-ODPXA compound exhibited anticancer properties in murine lymphoma; however, the anti-ovarian cancer (OC) mechanism has not yet been explored. Therefore, the present study evaluated whether 12-ODPXA reduces OC cell proliferation, metastasis, and invasion by downregulating pyruvate dehydrogenase kinase (PDK)4 expression.

Cell counting kit-8, colony formation, flow cytometry, wound healing, and transwell assays were performed to examine the effects of 12-ODPXA on OC cell proliferation, apoptosis, migration, and invasion. Transcriptome analysis was used to predict the changes in gene expression. Protein expression was determined using western blotting. Glucose, lactate, and adenosine triphosphate (ATP) test kits were used to measure glucose consumption and lactate and ATP production, respectively. Zebrafish xenograft models were constructed to elucidate the anti-OC effects of 12-ODPXA.

The 12-ODPXA compound inhibited OC cell proliferation, migration, invasion, and glycolysis while inducing cell apoptosis via downregulation of PDK4. In vivo experiments showed that 12-ODPXA suppressed tumor growth and migration in zebrafish.

Our data demonstrate that 12-ODPXA inhibits ovarian tumor growth and metastasis by downregulating PDK4, revealing the underlying mechanisms of action of 12-ODPXA in OC.

Microglia undergo two-stage activation in neurodegenerative diseases, known as disease-associated microglia (DAM). TREM2 mediates the DAM2 stage transition, but what regulates the first DAM1 stage transition is unknown. We report that glucose dyshomeostasis inhibits DAM1 activation and PKM2 plays a role. As in tumors, PKM2 was aberrantly elevated in both male and female human AD brains, but unlike in tumors, it is expressed as active tetramers, as well as among TREM2+ microglia surrounding plaques in 5XFAD male and female mice. snRNAseq analyses of microglia without Pkm2 in 5XFAD mice revealed significant increases in DAM1 markers in a distinct metabolic cluster, which is enriched in genes for glucose metabolism, DAM1, and AD risk. 5XFAD mice incidentally exhibited a significant reduction in amyloid pathology without microglial Pkm2 Surprisingly, microglia in 5XFAD without Pkm2 exhibited increases in glycolysis and spare respiratory capacity, which correlated with restoration of mitochondrial cristae alterations. In addition, in situ spatial metabolomics of plaque-bearing microglia revealed an increase in respiratory activity. These results together suggest that it is not only glycolytic but also respiratory inputs that are critical to the development of DAM signatures in 5XFAD mice.

Mechanistic understanding of transient exposures that lead to adverse health outcomes will enhance our ability to recognize biological signatures of disease. Here, we measured the transcriptomic and epigenomic alterations due to exposure to the metabolic reprogramming agent, dichloroacetic acid (DCA). Previously, we showed that exposure to DCA increased liver tumor incidence in B6C3F1 mice after continuous or early life exposures significantly over background level.

Using archived formalin-fixed liver samples, we utilized modern methodologies to measure gene expression and DNA methylation levels to link to previously generated phenotypic measures. Gene expression was measured by targeted RNA sequencing (TempO-seq 1500+ toxicity panel: 2754 total genes) in liver samples collected from 10-, 32-, 57-, and 78-week old mice exposed to deionized water (controls), 3.5 g/L DCA continuously in drinking water ("Direct" group), or DCA for 10-, 32-, or 57-weeks followed by deionized water until sample collection ("Stop" groups). Genome-scaled alterations in DNA methylation were measured by Reduced Representation Bisulfite Sequencing (RRBS) in 78-week liver samples for control, Direct, 10-week Stop DCA exposed mice.

Transcriptomic changes were most robust with concurrent or adjacent timepoints after exposure was withdrawn. We observed a similar pattern with DNA methylation alterations where we noted attenuated differentially methylated regions (DMRs) in the 10-week Stop DCA exposure groups compared to the Direct group at 78-weeks. Gene pathway analysis indicated cellular effects linked to increased oxidative metabolism, a primary mechanism of action for DCA, closer to exposure windows especially early in life. Conversely, many gene signatures and pathways reversed patterns later in life and reflected more pro-tumorigenic patterns for both current and prior DCA exposures. DNA methylation patterns correlated to early gene pathway perturbations, such as cellular signaling, regulation and metabolism, suggesting persistence in the epigenome and possible regulatory effects.

Liver metabolic reprogramming effects of DCA interacted with normal age mechanisms, increasing tumor burden with both continuous and prior DCA exposure in the male B6C3F1 rodent model.

Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.

Gastrointestinal (GI) cancer is one of the most severe types of cancer, with a significant impact on human health worldwide. Due to the urgent demand for more effective therapeutic strategies against GI cancers, novel research on metal ions for treating GI cancers has attracted increasing attention. Currently, with accumulating research on the relationship between metal ions and cancer therapy, several metal ions have been discovered to induce cell death. In particular, the three novel modes of cell death, including ferroptosis, cuproptosis, and calcicoptosis, have become focal points of research in the field of cancer. Meanwhile, other metal ions have also been found to trigger cell death through various mechanisms. Accordingly, this review focuses on the mechanisms of metal ion-induced cell death in GI cancers, hoping to provide theoretical support for further GI cancer therapies.

Ginsenoside Rh2 (G-Rh2), a steroidal compound extracted from roots of ginseng, has been extensively studied in tumor therapy. However, its specific regulatory mechanism in non-small cell lung cancer (NSCLC) is not well understood. Pyruvate dehydrogenase kinase 4 (PDK4), a central regulator of cellular energy metabolism, is highly expressed in various malignant tumors. We investigated the impact of G-Rh2 on the malignant progression of NSCLC and how it regulated PDK4 to influence tumor aerobic glycolysis and mitochondrial function.

We examined the inhibitory effect of G-Rh2 on NSCLC through I proliferation assay, migration assay and flow cytometry in vitro. Subsequently, we verified the ability of G-Rh2 to inhibit tumor growth and metastasis by constructing subcutaneous tumor and metastasis models in nude mice. Proteomics analysis was conducted to analyze the action pathways of G-Rh2. Additionally, we assessed glycolysis and mitochondrial function using seahorse, PET-CT, Western blot, and RT-qPCR.

Treatment with G-Rh2 significantly inhibited tumor proliferation and migration ability both in vitro and in vivo. Furthermore, G-Rh2 inhibited the tumor's aerobic glycolytic capacity, including glucose uptake and lactate production, through the HIF1-α/PDK4 pathway. Overexpression of PDK4 demonstrated that G-Rh2 targeted the inhibition of PDK4 expression, thereby restoring mitochondrial function, promoting reactive oxygen species (ROS) accumulation, and inducing apoptosis. When combined with sodium dichloroacetate, a PDK inhibitor, it complemented the inhibitory capacity of PDKs, acting synergistically as a detoxifier.

G-Rh2 could target and down-regulate the expression of HIF-1α, resulting in decreased expression of glycolytic enzymes and inhibition of aerobic glycolysis in tumors. Additionally, by directly targeting mitochondrial PDK, it elevated mitochondrial oxidative phosphorylation and enhanced ROS accumulation, thereby promoting tumor cells to undergo normal apoptotic processes.

Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest in its use for CRC prevention/therapy. We previously uncovered that acetate-induced mitochondrial-mediated apoptosis in CRC cells is significantly enhanced by the inhibition of the lysosomal protease cathepsin D (CatD), which indicates both mitochondria and the lysosome are involved in the regulation of acetate-induced apoptosis. Herein, we sought to determine whether mitochondrial function affects CatD apoptotic function. We found that enhancement of acetate-induced apoptosis by CatD inhibition depends on oligomycin A-sensitive respiration. Mechanistically, the potentiating effect is associated with an increase in cellular and mitochondrial superoxide anion accumulation and mitochondrial mass. Our results provide novel clues into the regulation of CatD function and the effect of tumor heterogeneity in the outcome of combined treatment using acetate and CatD inhibitors.

In this study, the folding of G-quadruplex (G4) from the telomeric DNA sequences having loop nucleobases of different chemical natures, numbers, and arrangements in 10 mM and 100 mM KCl salt conditions mimicking the cancerous and normal KCl salt microenvironments have been investigated. The data suggest that the structure and stability of the G4 are highly dependent on the KCl salt concentration. In general, the conformational flexibility of the folded G4 is higher in KCl salt relevant to cancer than in the normal case for any loop arrangements with the same number of nucleobases. The stability of the G4 decreases with the increase in the number of loop nucleobases for both salt conditions. However, the decrease in the stability of G4 having adenine in the loop region is significantly higher than the case of thymine, particularly more prominent in the KCl salt relevant to the cancer. The topology of the folded G4 and its stability also depend delicately on the permutation of the nucleobases in the loop and the salt concentrations for a particular sequence. The findings indicate that the structure and stability of G4 are noticeably different in KCl salt relevant to physiological and cancer conditions.

Multiple myeloma is a hematological malignancy that has evolved from antibody-secreting B lymphocytes. Like other types of cancers, myeloma cells have acquired functional capabilities which are referred to as "Hallmarks of Cancer", and one of their most important features is the metabolic disorders. Due to the high secretory load of the MM cells, the first-line medicine proteasome inhibitors have found their pronounced effects in MM cells for blocking the degradation of misfolded proteins, leading to their accumulation in the ER and overwhelming ER stress. Moreover, proteasome inhibitors have been reported to be effective in myeloma by targeting glucose, lipid, amino acid metabolism of MM cells. In this review, we have described the abnormal metabolism of the three major nutrients, such as glucose, lipid and amino acids, which participate in the cellular functions. We have described their roles in myeloma progression, how they could be exploited for therapeutic purposes, and current therapeutic strategies targeting these metabolites, hoping to uncover potential novel therapeutic targets and promote the development of future therapeutic approaches.

Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defense is a targetable vulnerability in cancer. Currently, only a few DHODH inhibitors have been utilized in clinical practice. To further enhance DHODH targeting, we introduced the mitochondrial targeting group triphenylphosphine (TPP) to brequinar (BRQ), a robust DHODH inhibitor, resulting in the creation of active molecule B2. This compound exhibits heightened anticancer activity, effectively inhibiting proliferation in various cancer cells, and restraining tumor growth in melanoma xenografts in mice. B2 achieves these effects by targeting DHODH, triggering the formation of reactive oxygen species (ROS), promoting mitochondrial lipid peroxidation, and inducing ferroptosis in B16F10 and A375 cells. Surprisingly, B2 significantly downregulates PD-L1 and alleviates immune suppression. Importantly, B2 exhibits no apparent adverse effects in mice. Collectively, these findings highlight that enhancing the mitochondrial targeting capability of the DHODH inhibitor is a promising therapeutic approach for melanoma treatment.

Chordomas are clinically aggressive tumors with a high rate of disease progression despite maximal therapy. Given the limited therapeutic options available, there remains an urgent need for the development of novel therapies to improve clinical outcomes. Cell surface proteins are attractive therapeutic targets yet are challenging to profile with common methods. Four chordoma cell lines were analyzed by quantitative proteomics using a differential ultracentrifugation organellar fractionation approach. A subtractive proteomics strategy was applied to select proteins that are plasma membrane enriched. Systematic data integration prioritized PLA2R1 (secretory phospholipase A2 receptor-PLA2R1) as a chordoma-enriched surface protein. The expression profile of PLA2R1 was validated across chordoma cell lines, patient surgical tissue samples, and normal tissue lysates via immunoblotting. PLA2R1 expression was further validated by immunohistochemical analysis in a richly annotated cohort of 25-patient tissues. Immunohistochemistry analysis revealed that elevated expression of PLA2R1 is correlated with poor prognosis. Using siRNA- and CRISPR/Cas9-mediated knockdown of PLA2R1, we demonstrated significant inhibition of 2D, 3D and in vivo chordoma growth. PLA2R1 depletion resulted in cell cycle defects and metabolic rewiring via the MAPK signaling pathway, suggesting that PLA2R1 plays an essential role in chordoma biology. We have characterized the proteome of four chordoma cell lines and uncovered PLA2R1 as a novel cell-surface protein required for chordoma cell survival and association with patient outcome.

Metabolism is reprogrammed in a variety of cancer cells to ensure their rapid proliferation. Cancer cells prefer to utilize glycolysis to produce energy as well as to provide large amounts of precursors for their division. In this process, cancer cells inhibit the activity of pyruvate dehydrogenase complex (PDC) by upregulating the expression of pyruvate dehydrogenase kinases (PDKs). Inhibiting the activity of PDKs in cancer cells can effectively block this metabolic transition in cancer cells, while also activating mitochondrial oxidative metabolism and promoting apoptosis of cancer cells. To this day, the study of PDKs inhibitors has become one of the research hotspots in the field of medicinal chemistry. Novel structures targeting PDKs are constantly being discovered, and some inhibitors have entered the clinical research stage. Here, we reviewed the research progress of PDKs inhibitors in recent years and classified them according to the PDKs binding sites they acted on, aiming to summarize the structural characteristics of inhibitors acting on different binding sites and explore their clinical application value. Finally, the shortcomings of some PDKs inhibitors and the further development direction of PDKs inhibitors are discussed.

In humans and animals, the pyruvate dehydrogenase kinase (PDK) family proteins (PDKs 1-4) are excessively activated in metabolic disorders such as obesity, diabetes, and cancer, inhibiting the activity of pyruvate dehydrogenase (PDH) which plays a crucial role in energy and fatty acid metabolism and impairing its function. Intervention and regulation of PDH activity have become important research approaches for the treatment of various metabolic disorders. In this study, a small molecule (g25) targeting PDKs and activating PDH, was identified through multi-level computational screening methods. In vivo and in vitro experiments have shown that g25 activated the activity of PDH and reduced plasma lactate and triglyceride level. Besides, g25 significantly decreased hepatic fat deposition in a diet-induced obesity mouse model. Furthermore, g25 enhanced the tumor-inhibiting activity of cisplatin when used in combination. Molecular dynamics simulations and in vitro kinase assay also revealed the specificity of g25 towards PDK2. Overall, these findings emphasize the importance of targeting the PDK/PDH axis to regulate PDH enzyme activity in the treatment of metabolic disorders, providing directions for future related research. This study provides a possible lead compound for the PDK/PDH axis related diseases and offers insights into the regulatory mechanisms of this pathway in diseases.

Although Otto Warburg may be right about the role of glycolysis versus OXPHOS in cancer metabolism, it remains unclear whether an altered metabolism is causative or correlative and is the main driver or a mere passenger in the pathogenesis of cancer. Currently, most of our successful treatments are designed to eliminate non-cancer stem cells (non-CSCs) such as differentiated cancer cells. When the treatments also happen to control CSCs or the stem-ness niche, it is often unintended, unexpected, or undetected for lack of a pertinent theory about the origin of cancer that clarifies whether cancer is a metabolic, genetic, or stem cell disease. Perhaps cellular context matters. After all, metabolic activity may be different in different cell types and their respective microenvironments-whether it is in a normal progenitor stem cell vs. progeny differentiated cell and whether it is in a malignant CSC vs. non-CSC. In this perspective, we re-examine different types of cellular metabolism, e.g., glycolytic vs. mitochondrial, of glucose, glutamine, arginine, and fatty acids in CSCs and non-CSCs. We revisit the Warburg effect, an obesity epidemic, the aspartame story, and a ketogenic diet. We propose that a pertinent scientific theory about the origin of cancer and of cancer metabolism influences the direction of cancer research as well as the design of drug versus therapy development in cancer care.

Triple-negative breast cancer (TNBC) remains the most challenging subtype of breast cancer and lacks definite treatment targets. Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to cancer progression. PFKP is a rate-limiting enzyme involved in aerobic glycolysis, which is overexpressed in various types of cancers. However, the underlying mechanisms and roles of the posttranslational modification of PFKP in TNBC remain unknown.

To explore whether PFKP protein has a potential role in the progression of TNBC, protein levels of PFKP in TNBC and normal breast tissues were examined by CPTAC database analysis, immunohistochemistry staining (IHC), and western blotting assay. Further CCK-8 assay, colony formation assay, EDU incorporation assay, and tumor xenograft experiments were used to detect the effect of PFKP on TNBC progression. To clarify the role of the USP5-PFKP pathway in TNBC progression, ubiquitin assay, co-immunoprecipitation (Co-IP), mass spectrometry-based protein identification, western blotting assay, immunofluorescence microscopy, in vitro binding assay, and glycolysis assay were conducted.

Herein, we showed that PFKP protein was highly expressed in TNBC, which was associated with TNBC progression and poor prognosis of patients. In addition, we demonstrated that PFKP depletion significantly inhibited the TNBC progression in vitro and in vivo. Importantly, we identified that PFKP was a bona fide target of deubiquitinase USP5, and the USP5-mediated deubiquitination and stabilization of PFKP were essential for cancer cell aerobic glycolysis and TNBC progression. Moreover, we found a strong positive correlation between the expression of USP5 and PFKP in TNBC samples. Notably, the high expression of USP5 and PFKP was significantly correlated with poor clinical outcomes.

Our study established the USP5-PFKP axis as an important regulatory mechanism of TNBC progression and provided a rationale for future therapeutic interventions in the treatment of TNBC.