PPAR-γ agonists reactivate the ALDOC-NR2F1 axis to enhance sensitivity to temozolomide and suppress glioblastoma progression.

Glioblastoma (GBM) is a type of brain cancer categorized as a high-grade glioma. GBM is characterized by limited treatment options, low patient survival rates, and abnormal serotonin metabolism. Previous studies have investigated the tumor suppressor function of aldolase C (ALDOC), a glycolytic enzyme in GBM. However, it is unclear how ALDOC regulates production of serotonin and its associated receptors, HTRs. In this study, we analyzed ALDOC mRNA levels and methylation status using sequencing data and in silico datasets. Furthermore, we investigated pathways, phenotypes, and drug effects using cell and mouse models. Our results suggest that loss of ALDOC function in GBM promotes tumor cell invasion and migration. We observed that hypermethylation, which results in loss of ALDOC expression, is associated with serotonin hypersecretion and the inhibition of PPAR-γ signaling. Using several omics datasets, we present evidence that ALDOC regulates serotonin levels and safeguards PPAR-γ against serotonin metabolism mediated by 5-HT, which leads to a reduction in PPAR-γ expression. PPAR-γ activation inhibits serotonin release by HTR and diminishes GBM tumor growth in our cellular and animal models. Importantly, research has demonstrated that PPAR-γ agonists prolong animal survival rates and increase the efficacy of temozolomide in an orthotopic brain model of GBM. The relationship and function of the ALDOC-PPAR-γ axis could serve as a potential prognostic indicator. Furthermore, PPAR-γ agonists offer a new treatment alternative for glioblastoma multiforme (GBM).

CD47-mediated immune evasion in early-stage lung cancer progression.

Alveolar and interstitial macrophages play crucial roles in eradicating pathogens and transformed cells in the lungs. The immune checkpoint CD47, found on normal and malignant cells, interacts with the SIRPα ligand on macrophages, inhibiting phagocytosis, antigen presentation, and promoting immune evasion. In this study, we demonstrated that CD47 is not only a transmembrane protein, but that it is also highly concentrated in extracellular vesicles from lung cancer cell lines and patient plasma. Abundant CD47 was observed in the cytoplasm of lung cancer cells, aligning with our finding that it was packed into extracellular vesicles for physiological and pathological functions. In our clinical cohort, extracellular vesicle CD47 was significantly higher in the patients with early-stage lung cancer, emphasizing innate immunity inactivation in early tumor progression. To validate our hypothesis, we established an orthotopic xenograft model mimicking lung cancer development, which showed increased serum soluble CD47 and elevated IL-10/TNF-α ratio, indicating an immune-suppressive tumor microenvironment. CD47 expression led to reduced tumor-infiltrating macrophages during progression, while there was a post-xenograft increase in tumor-associated macrophages. In conclusion, CD47 is pivotal in early lung cancer progression, with soluble CD47 emerging as a key pathological effector.

Recent advances in near-infrared I/II persistent luminescent nanoparticles for biosensing and bioimaging in cancer analysis.

Photoluminescent materials (PLNs) are photoluminescent materials that can absorb external excitation light, store it, and slowly release it in the form of light in the dark to achieve long-term luminescence. Developing near-infrared (NIR) PLNs is critical to improving long-afterglow luminescent materials. Because they excite in vitro, NIR-PLNs have the potential to avoid interference from in vivo autofluorescence in biomedical applications. These materials are promising for biosensing and bioimaging applications by exploiting the near-infrared biological window. First, we discuss the biomedical applications of PLNs in the first near-infrared window (NIR-I, 700-900 nm), which have been widely developed and specifically introduce biosensors and imaging reagents. However, the light in this area still suffers from significant light scattering and tissue autofluorescence, which will affect the imaging quality. Over time, fluorescence imaging technology in the second near-infrared window (NIR-II, 1000-1700 nm) has also begun to develop rapidly. NIR-II fluorescence imaging has the advantages of low light scattering loss, high tissue penetration depth, high imaging resolution, and high signal-to-noise ratio, and it shows broad application prospects in biological analysis and medical diagnosis. This critical review collected and sorted articles from the past 5 years and introduced their respective fluorescence imaging technologies and backgrounds based on the definitions of NIR-I and NIR-II. We also analyzed the current advantages and dilemmas that remain to be solved. Herein, we also suggested specific approaches NIR-PLNs can use to improve the quality and be more applicable in cancer research.

Dawn era for revisited cancer therapy by innate immune system and immune checkpoint inhibitors.

Immunotherapy is a promising therapeutic strategy for cancer. However, it shows limited efficacy against certain tumor types. The activation of innate immunity can suppress tumors by mitigating inflammatory and malignant behaviors through immune surveillance. The tumor microenvironment, which is composed of immune cells and cancer cells, plays a crucial role in determining the outcomes of immunotherapy. Relying solely on immune checkpoint inhibitors is not an optimal approach. Instead, there is a need to consider the use of a combination of immune checkpoint inhibitors with other modulators of the innate immune system to improve the tumor microenvironment. This can be achieved through methods such as immune cell antigen presentation and recognition. In this review, we delve into the significance of innate immune cells in tumor regression, as well as the role of the interaction of tumor cells with innate immune cells in evading host immune surveillance. These findings pave the way for the next chapter in the field of immunotherapy.

ALDOA coordinates PDE3A through the ß-catenin/ID3 axis to stimulate cancer metastasis and M2 polarization in lung cancer with EGFR mutations.

Lung cancer has a high incidence rate and requires more effective treatment strategies and drug options for clinical patients. EGFR is a common genetic alteration event in lung cancer that affects patient survival and drug strategy. Our study discovered aberrant aldolase A (ALDOA) expression and dysfunction in lung cancer patients with EGFR mutations. In addition to investigating relevant metabolic processes like glucose uptake, lactate production, and ATPase activity, we examined multi-omics profiles (transcriptomics, proteomics, and pull-down assays). It was observed that phosphodiesterase 3A (PDE3A) enzyme and ALDOA exhibit correlation, and furthermore, they impact M2 macrophage polarization through ß-catenin and downstream ID3. In addition to demonstrating the aforementioned mechanism of action, our experiments discovered that the PDE3 inhibitor trequinsin has a substantial impact on lung cancer cell lines with EGFR mutants. The trequinsin medication was found to decrease the M2 macrophage polarization status and several cancer phenotypes, in addition to transduction. These findings have potential prognostic and therapeutic applications for clinical patients with EGFR mutation and lung cancer.

Low Expression of A3C and PLP2 Indicating a Favorable Prognosis in Human Gliomas.

The roles of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3C (A3C) in various human malignancies are not consistent. A3C expression is correlated with early-stage breast cancer and is presented as a good prognostic factor; however, it induces fewer therapeutic effects of cytotoxic drugs in low-grade gliomas. To explore the impact of A3C on gliomas, a statistical analysis of several public databases was conducted. The results showed that enhanced A3C expression was associated with advanced tumor grades and poor expression of prognostic factors. Similarly, our in vitro study revealed that glioblastoma (GBM) cell lines had higher A3C mRNA and protein expression than that of normal brain tissue cDNA and lysates. We first performed an immunohistochemical stain (IHC) to prove that gliomas with high A3C expression presented the wild type-Isocitrate dehydrogenase 1 (IDH1), and they had an unfavorable prognosis in human glioma tissues. In addition, the oncological factors associated with A3C expression suggested that DNA repair pathways are important mechanisms for inducing tumorigenesis and chemoresistance in gliomas. Moreover, a significant correlation was observed between A3C expression and proteolipid protein 2  (PLP2). Reactive oxygen species (ROS) -activated PLP2 prevents DNA damage-induced cell apoptosis. Compared to high immunostaining scores for A3C and/or PLP2 expression, combined low immunostaining scores for A3C and PLP2 correlated with improved survival in gliomas; however, the detailed mechanism is to be elucidated. In conclusion, our results not only confirmed A3C played an important role in glioma development, but the A3C IHC test could successfully predict the therapeutic effects and disease prognosis.

Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation.

Cholangiocarcinoma (CCA) exhibits aggressive biological behavior and a poor prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line chemotherapy for advanced CCA but has a response rate of only 20-30%. Therefore, investigating treatments to overcome GEM resistance in advanced CCA is crucial. Among mucin (MUC) family members, MUC4 showed the greatest increase in the resistant versus parental sublines. MUC4 was upregulated in whole-cell lysates and conditioned media from gemcitabine-resistant (GR) CCA sublines. MUC4 mediated GEM resistance by activating AKT signaling in GR CCA cells. The MUC4-AKT axis induced BAX S184 phosphorylation to inhibit apoptosis and downregulated GEM transporter human equilibrative nucleoside transporter 1 (hENT1) expression. The combination of AKT inhibitors and GEM or afatinib overcame GEM resistance in CCA. In vivo, capivasertib (an AKT inhibitor) increased GEM sensitivity in GR cells. MUC4 promoted EGFR and HER2 activation to mediate GEM resistance. Finally, MUC4 expression in patient plasma correlated with MUC4 expression. Paraffin-embedded specimens from non-responders expressed significantly more MUC4 than did those from responders, and this upregulation was associated with poor progression-free survival and overall survival. In GR CCA, high MUC4 expression promotes sustained EGFR/HER2 signaling and AKT activation. The combination of AKT inhibitors with GEM or afatinib might overcome GEM resistance.

Glucose transporter 4: Insulin response mastermind, glycolysis catalyst and treatment direction for cancer progression.

The glucose transporter family (GLUT) consists of fourteen members. It is responsible for glucose homeostasis and glucose transport from the extracellular space to the cell cytoplasm to further cascade catalysis. GLUT proteins are encoded by the solute carrier family 2 (SLC2) genes and are members of the major facilitator superfamily of membrane transporters. Moreover, different GLUTs also have their transporter kinetics and distribution, so each GLUT member has its uniqueness and importance to play essential roles in human physiology. Evidence from many studies in the field of diabetes showed that GLUT4 travels between the plasma membrane and intracellular vesicles (GLUT4-storage vesicles, GSVs) and that the PI3K/Akt pathway regulates this activity in an insulin-dependent manner or by the AMPK pathway in response to muscle contraction. Moreover, some published results also pointed out that GLUT4 mediates insulin-dependent glucose uptake. Thus, dysfunction of GLUT4 can induce insulin resistance, metabolic reprogramming in diverse chronic diseases, inflammation, and cancer. In addition to the relationship between GLUT4 and insulin response, recent studies also referred to the potential upstream transcription factors that can bind to the promoter region of GLUT4 to regulating downstream signals. Combined all of the evidence, we conclude that GLUT4 has shown valuable unknown functions and is of clinical significance in cancers, which deserves our in-depth discussion and design compounds by structure basis to achieve therapeutic effects. Thus, we intend to write up a most updated review manuscript to include the most recent and critical research findings elucidating how and why GLUT4 plays an essential role in carcinogenesis, which may have broad interests and impacts on this field.

The activation of EP300 by F11R leads to EMT and acts as a prognostic factor in triple-negative breast cancers.

Cancer progression is influenced by junctional adhesion molecule (JAM) family members. The relationship between JAM family members and different types of cancer was examined using The Cancer Genome Atlas dataset. mRNA levels of the F11R (F11 receptor) in tumours were inversely correlated to the expression of JAM-2 and JAM-3. This relationship was unique to breast cancer (BCa) and was associated with poor prognosis (p = 0.024, hazard ratio = 1.44 [1.05-1.99]). A 50-gene molecular signature (prediction analysis of microarray 50) was used to subtype BCa. F11R mRNA expression significantly increased in human epidermal growth factor receptor 2 (HER2)-enriched (p = 0.0035) and basal-like BCa tumours (p = 0.0005). We evaluated F11R protein levels in two different compositions of BCa subtype patient tissue array cohorts to determine the relationship between BCa subtype and prognosis. Immunohistochemistry staining revealed that a high F11R protein level was associated with poor overall survival (p < 0.001; Taipei Medical University [TMU] cohort, p < 0.001; Kaohsiung Veterans General Hospital [KVGH] cohort) or disease-free survival (p < 0.001 [TMU cohort], p = 0.034 [KVGH cohort]) in patients with BCa. Comparison of F11R levels in different subtypes revealed the association of poor prognosis with high levels of F11R among luminal (p < 0.001 [TMU cohort], p = 0.027 [KVGH cohort]), HER2 positive (p = 0.018 [TMU cohort], p = 0.037 [KVGH cohort]), and triple-negative (p = 0.013 [TMU cohort], p = 0.037 [KVGH cohort]) BCa. F11R-based RNA microarray analysis and Ingenuity Pathway Analysis were successful in profiling the detailed gene ontology of triple-negative BCa cells regulated by F11R. The EP300 transcription factor was highly correlated with F11R in BCa (R = 0.51, p < 0.001). By analysing these F11R-affected molecules with the L1000CDs datasets, we were able to predict some repurposing drugs for potential application in F11R-positive BCa treatment.

The cytoplasmic expression of FSTL3 correlates with colorectal cancer progression, metastasis status and prognosis.

Follistatin-like (FSTL) family members are associated with cancer progression. However, differences between FSTL members with identical cancer types have not been systematically investigated. Among the most malignant tumours worldwide, colorectal cancer (CRC) has high metastatic potential and chemoresistance, which makes it challenging to treat. A systematic examination of the relationship between the expression of FSTL family members in CRC will provide valuable information for prognosis and therapeutic development. Based on large cohort survival analyses, we determined that FSTL3 was associated with a significantly worse prognosis in CRC at the RNA and protein levels. Immunohistochemistry staining of CRC specimens revealed that FSTL3 expression levels in the cytosol were significantly associated with a poor prognosis in terms of overall and disease-free survival. Molecular simulation analysis showed that FSTL3 participated in multiple cell motility signalling pathways via the TGF-ß1/TWIST1 axis to control CRC metastasis. The findings provide evidence of the significance of FSTL3 in the oncogenesis and metastasis of CRC. FSTL3 may be useful as a diagnostic or prognostic biomarker, and as a potential therapeutic target.

Overexpression of synaptic vesicle protein Rab GTPase 3C promotes vesicular exocytosis and drug resistance in colorectal cancer cells.

Rab GTPase 3C (RAB3C) is a peripheral membrane protein that is involved in membrane trafficking (vesicle formation) and cell movement. Recently, researchers have noted the exocytosis of RAB proteins, and their dysregulation is correlated with drug resistance and the altered tumor microenvironment in tumorigenesis. However, the molecular mechanisms of exocytotic RABs in the carcinogenicity of colorectal cancer (CRC) remain unknown. Researchers have used various in silico datasets to evaluate the expression profiles of RAB family members. We confirmed that RAB3C plays a key role in CRC progression. Its overexpression promotes exocytosis and is related to the resistance to several chemotherapeutic drugs. We established a proteomic dataset based on RAB3C, and found that dystrophin is one of the proteins that is upregulated with the overexpression of RAB3C. According to our results, RAB3C-induced dystrophin expression promotes vesicle formation and packaging. A connectivity map predicted that the cannabinoid receptor 2 (CB2) agonists reverse RAB3C-associated drug resistance, and that these agonists have synergistic effects when combined with standard chemotherapy regimens. Moreover, we found high dystrophin expression levels in CRC patients with poor survival outcomes. A combination of the dystrophin and RAB3C expression profiles can serve as an independent prognostic factor in CRC and is associated with several clinicopathological parameters. In addition, the RAB3C-dystrophin axis is positively correlated with the phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) genetic alterations in CRC patients. These findings can be used to provide novel combined therapeutic options for the treatment of CRC.

Gold Nanoparticles as a Biosensor for Cancer Biomarker Determination.

Molecular biology applications based on gold nanotechnology have revolutionary impacts, especially in diagnosing and treating molecular and cellular levels. The combination of plasmonic resonance, biochemistry, and optoelectronic engineering has increased the detection of molecules and the possibility of atoms. These advantages have brought medical research to the cellular level for application potential. Many research groups are working towards this. The superior analytical properties of gold nanoparticles can not only be used as an effective drug screening instrument for gene sequencing in new drug development but also as an essential tool for detecting physiological functions, such as blood glucose, antigen-antibody analysis, etc. The review introduces the principles of biomedical sensing systems, the principles of nanomaterial analysis applied to biomedicine at home and abroad, and the chemical surface modification of various gold nanoparticles.

A G-quadruplex stabilizer, CX-5461 combined with two immune checkpoint inhibitors enhances in vivo therapeutic efficacy by increasing PD-L1 expression in colorectal cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy can improve the limited efficacy of colorectal cancer (CRC) immunotherapy. CX-5461 causes substantial DNA damage and genomic instability and can increase ICIs' therapeutic efficacies through tumor microenvironment alteration. RESULTS: We analyzed whether CX-5461 enhances ICIs' effects in CRC and discovered that CX-5461 causes severe DNA damage, including cytosolic dsDNA appearance, in various human and mouse CRC cells. Our bioinformatics analysis predicted CX-5461-based interferon (IFN) signaling pathway activation in these cells, which was verified by the finding that CX-5461 induces IFN-α and IFN-ß secretion in these cells. Next, cGAMP, phospho-IRF3, CCL5, and CXCL10 levels exhibited significant posttreatment increases in CRC cells, indicating that CX-5461 activates the cGAS-STING-IFN pathway. CX-5461 also enhanced PD-L1 expression through STAT1 activation. CX-5461 alone inhibited tumor growth and prolonged survival in mice. CX-5461+anti-PD-1 or anti-PD-L1 alone exhibited synergistic growth-suppressive effects against CRC and breast cancer. CX-5461 alone or CX-5461+anti-PD-1 increased cytotoxic T-cell numbers and reduced myeloid-derived suppressor cell numbers in mouse spleens. CONCLUSIONS: Therefore, clinically, CX-5461 combined with ICIs for CRC therapy warrants consideration because CX-5461 can turn cold tumors into hot ones.

Iron-Based Ceramic Composite Nanomaterials for Magnetic Fluid Hyperthermia and Drug Delivery.

Because of the unique physicochemical properties of magnetic iron-based nanoparticles, such as superparamagnetism, high saturation magnetization, and high effective surface area, they have been applied in biomedical fields such as diagnostic imaging, disease treatment, and biochemical separation. Iron-based nanoparticles have been used in magnetic resonance imaging (MRI) to produce clearer and more detailed images, and they have therapeutic applications in magnetic fluid hyperthermia (MFH). In recent years, researchers have used clay minerals, such as ceramic materials with iron-based nanoparticles, to construct nanocomposite materials with enhanced saturation, magnetization, and thermal effects. Owing to their unique structure and large specific surface area, iron-based nanoparticles can be homogenized by adding different proportions of ceramic minerals before and after modification to enhance saturation magnetization. In this review, we assess the potential to improve the magnetic properties of iron-based nanoparticles and in the preparation of multifunctional composite materials through their combination with ceramic materials. We demonstrate the potential of ferromagnetic enhancement and multifunctional composite materials for MRI diagnosis, drug delivery, MFH therapy, and cellular imaging applications.

Application of Metabolic Reprogramming to Cancer Imaging and Diagnosis.

Cellular metabolism governs the signaling that supports physiological mechanisms and homeostasis in an individual, including neuronal transmission, wound healing, and circadian clock manipulation. Various factors have been linked to abnormal metabolic reprogramming, including gene mutations, epigenetic modifications, altered protein epitopes, and their involvement in the development of disease, including cancer. The presence of multiple distinct hallmarks and the resulting cellular reprogramming process have gradually revealed that these metabolism-related molecules may be able to be used to track or prevent the progression of cancer. Consequently, translational medicines have been developed using metabolic substrates, precursors, and other products depending on their biochemical mechanism of action. It is important to note that these metabolic analogs can also be used for imaging and therapeutic purposes in addition to competing for metabolic functions. In particular, due to their isotopic labeling, these compounds may also be used to localize and visualize tumor cells after uptake. In this review, the current development status, applicability, and limitations of compounds targeting metabolic reprogramming are described, as well as the imaging platforms that are most suitable for each compound and the types of cancer to which they are most appropriate.

The CHST11 gene is linked to lung cancer and pulmonary fibrosis.

BACKGROUND: The abnormal modification of chondroitin sulfate is one of the leading causes of disease, including cancer progression. During chondroitin sulfate biosynthesis, the CHST11 enzyme plays a vital role in its modification, but its role in cancer is not fully understood. Therefore, understanding the relationship between CHST11 and pulmonary-related diseases through clinically relevant information may be useful for diagnosis or treatment. METHODS: A variety of pulmonary fibrosis clinical gene expression omnibus (GEO) datasets were used to assess the association between CHST11-related manifestations and fibrosis. Multiple lung cancer-related databases, including The Cancer Genome Atlas, GEO datasets, UCSC Xena, GEPIA2, Cbioportal and ingenuity pathway analysis were used to evaluate the clinical correlation between CHST11 and lung cancer and potential molecular mechanisms. For drug repurposing prediction, the molecules that correlated with CHST11 were subjected to the LINCS L1000 algorithm. A variety of in vitro assays were performed to evaluate the in-silico models, including RNA and protein expression, proliferation, migration and invasion. RESULTS: Clinical analyses indicate that the levels of CHST11 are significantly elevated in cases of pulmonary-related diseases, including fibrosis and lung cancer. According to multiple lung cancer cohorts, CHST11 is the only member of the carbohydrate sulfotransferase family associated with overall survival for lung adenocarcinomas, and it is highly related to smoking-induced lung cancer patients. Based on the results of in vitro experiments, CHST11 expression contributes to tumor malignancy and promotes multiple fibrotic activators. Correlation-based ingenuity pathway analysis indicated that CHST11-related molecules contributed to pulmonary fibrosis or lung adenocarcinomas via similar upstream stimulators. Based on known molecular regulatory relationships, CHST11 has been associated with the regulation of TGF-ß and INFγ as important molecules contributing to fibrosis and cancer progression. Interestingly, WordCloud analysis revealed that CHST11-related molecules are involved in regulation primarily by integrin signaling, and these relationships were consistently reflected in the analysis of cell lines and the clinical correlation. A CHST11 signature-based drug repurposing analysis demonstrated that the CHST11/integrin axis could be targeted by AG-1478 (Tyrphostin AG 1478), brefeldin A, geldanamycin and importazole. CONCLUSIONS: This study provides the first demonstration that CHST11 may be used as a biomarker for pulmonary fibrosis or lung cancer, and the levels of CHST11 were increased by TGF-ß and INFγ. The molecular simulation analyses demonstrate that the CHST11/integrin axis is a potential therapeutic target for treating lung cancer.

Novel monodisperse FePt nanocomposites for T2-weighted magnetic resonance imaging: biomedical theranostics applications.

Given the high incidence and mortality of cancer, current research is focused on designing efficient diagnostic methods. At present, clinical diagnoses are made based on X-ray, computed tomography, magnetic resonance imaging (MRI), ultrasound, and fiber optic endoscopy. MRI is a powerful diagnostic tool because it is non-invasive, has a high spatial resolution, uses non-ionizing radiation, and has good soft-tissue contrast. However, the long relaxation time of water protons may result in the inability to distinguish different tissues. To overcome this drawback of MRI, magnetic resonance contrast agents can enhance the contrast, improve the sensitivity of MRI-based diagnoses, increase the success rate of surgery, and reduce tumor recurrence. This review focuses on using iron-platinum (FePt) nanoparticles (NPs) in T2-weighted MRI to detect tumor location based on dark-field changes. In addition, existing methods for optimizing and improving FePt NPs are reviewed, and the MRI applications of FePt NPs are discussed. FePT NPs are expected to strengthen MRI resolution, thereby helping to inhibit tumor development.

Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells.

Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the "Warburg effect". Energy-metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the "Warburg effect", tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.

The aberrant cancer metabolic gene carbohydrate sulfotransferase 11 promotes non-small cell lung cancer cell metastasis via dysregulation of ceruloplasmin and intracellular iron balance.

Aberrant metabolism has been proposed as one of the emerging hallmarks of cancer. However, the interplay between metabolic disorders and cancer metastasis remains to be defined. To explore the sophisticated metabolic processes during metastatic progression, we analyzed differentially expressed metabolic genes during the epithelial-mesenchymal transition (EMT) of lung cancer cells and defined the EMT-associated metabolic gene signature in lung adenocarcinoma patients. We found that the glycosaminoglycan (GAG)-chondroitin sulfate (CS) biosynthesis pathway was upregulated in the mesenchymal state of lung cancer and associated with poor prognosis. Notably, carbohydrate sulfotransferase 11 (CHST11), a crucial CS biosynthetic enzyme, was confirmed as a poor prognosis marker in non-small cell lung cancer (NSCLC) by immunohistochemical analysis. Moreover, forced CHST11 expression promoted invasion and metastasis, which was abolished by depleting the final product of CS biosynthesis by chondroitinase ABC treatment or active-domain negative CHST11. In vivo metastasis mouse models showed that CHST11 increased lung colonies number and sulfated mucosubstance expression. Furthermore, microarray analysis revealed ceruloplasmin (CP), which facilitated iron metabolism, was the downstream effector of CHST11. CP was upregulated by CHST11 through interferon-γ signaling pathway stimulation and related to unfavorable prognosis. Both forced CP expression and long-term iron treatment increased invasion and lung colony formation. Furthermore, we found 3-AP, an iron chelator, hampered the CHST11-induced metastasis. Our findings implicate that the novel CHST11-CP-iron axis enhances EMT and may serve as a new therapeutic target to treat NSCLC patients.