GLUT1-targeted Nano-delivery System for Active Ingredients of Traditional Chinese Medicine：A Review / 中国实验方剂学杂志

Tumor cells use glycolysis to provide material and energy under hypoxic conditions to meet the energy requirements for rapid growth and proliferation， namely the Warburg effect. Even under aerobic conditions， tumor cells mainly rely on glycolysis to provide energy. Therefore， glucose transporter protein 1（GLUT1）， which is involved in the process of glucose metabolism， plays an important role in tumorigenesis， development and drug resistance， and is considered to be one of the important targets in the treatment of malignant tumors. In recent years， research on tumor glucose metabolism has gradually become a hot spot. It has been shown that various factors are involved in the regulation of tumor energy metabolism， among which the role of GLUT1 is the most critical. In this paper， the authors reviewed the latest research progress of GLUT1-targeted traditional Chinese medicine（TCM） active ingredient nano-delivery system in tumor therapy， aiming to reveal the feasibility and effectiveness of this system in the delivery of chemotherapeutic drugs. The GLUT1-targeted TCM active ingredient nano-delivery system can overcome the bottleneck of the traditional targeting strategy as well as the high-permeability long retention（EPR） effect. In summary， the authors believe that the GLUT1-targeted TCM active ingredient nano-delivery system provides a new strategy for targeted treatment of tumors and has a broad application prospect in tumor prevention and treatment.

Role of Aerobic Glycolysis in Breast Cancer and Traditional Chinese Medicine Intervention： A Review / 中国实验方剂学杂志

Breast cancer has become the malignant tumor with the highest incidence rate. Although the emergence of new drugs has prolonged the overall survival of breast cancer patients， it still possesses a high recurrence and metastasis rate due to tumor heterogeneity and drug resistance. Glucose is the main source of energy metabolism for breast cancer cells， and the glucose metabolism of breast cancer cells is significantly different from that of normal breast cells. The high energy demand and rapid growth of breast cancer cells make their demand for glucose much higher than that of normal cells. Moreover， even under aerobic conditions， the glycolytic effect of breast cancer cells will be significantly enhanced to meet the high energy metabolism demand of breast cancer cells. The main reason for the enhanced glycolytic effect of breast cancer cells is the enhanced activity of glycolysis-related enzymes and regulatory factors， including pyruvate kinase， hexokinase， phosphofructokinase， lactate dehydrogenase， and glucose transporter protein. The metabolism process of glycolysis in breast cancer cells can be regulated by interfering with the activity of these enzymes and regulatory factors， thus inhibiting the proliferation of breast cancer， promoting apoptosis， and reversing drug resistance， invasion， and metastasis. Traditional Chinese medicine （TCM） has a long history of treating breast cancer and has made significant achievements in the aspects of anti-recurrence， metastasis， and drug resistance. In recent years， more and more research related to the intervention of aerobic glycolysis in breast cancer by TCM monomers， single-flavored TCM， and compounds has been conducted and has made great achievements. In addition， a large number of in vivo and in vitro experiments have shown that aerobic glycolysis is an important potential target for the treatment of breast cancer by TCM， but there is a lack of a comprehensive review and summary. On this basis， this paper elaborated on the roles of key targets in aerobic glycolysis and breast cancer and summarized the relevant studies on the treatment of breast cancer by intervention of glycolysis with TCM， with a view to providing new ideas for further research.

NUDT5 promotes the growth, metastasis, and Warburg effect of IDH wild-type glioblastoma multiforme cells by upregulating TRIM47

@#Objective: To explore the regulatory mechanism of NUDT5 in glioblastoma multiforme (GBM). Methods: GEPIA database was used to predict the expressions of NUDT5 and tripartite motif family proteins 47 (TRIM47) in GBM patients. RT-qPCR and Western blot analyses were performed to examine NUDT5 expression in GBM cells. LN-229 cell proliferation, migration as well as invasion were estimated by CCK- 8, colony formation, wound healing, and Transwell assays following interference with NUDT5. ECAR assay, L-lactic acid kit, glucose detection kit, and ATP detection kit were applied for the detection of glycolysis-related indexes. Co-immunoprecipitation experiment was carried out to verify the relationship between NUDT5 and TRIM47. Results: GEPIA database showed that NUDT5 expression was significantly increased in GBM patients. Inhibiting the expression of NUDT5 in GBM cells significantly suppressed the viability, proliferation, invasion, migration, and glycolysis of GBM cells. Moreover, TRIM47 was highly expressed in GBM cells and interacted with NUDT5. Overexpression of TRIM47 partially reversed the inhibitory effect of NUDT5 downregulation on the proliferation, metastasis, and glycolysis of GBM cells. Conclusions: NUDT5 promotes the growth, metastasis, and Warburg effect of GBM cells by upregulating TRIM47. Both NUDT5 and TRIM47 can be used as targets for GMB treatment.

Expression and Significance of Lactate Dehydrogenase A in Renal Cell Carcinoma / 中山大学学报(医学科学版)

ObjectiveTo analyze the expression of Lactate dehydrogenase A（LDHA） in both renal cell carcinoma （RCC） tissue and RCC cell lines， and to investigate the impact of LDHA expression on the progression of RCC. MethodsFrom June 2018 to June 2022， totally 52 cases of RCC tissue samples and 49 cases of para-cancerous tissue samples were collected through surgical procedures from our hospital. LDHA expression was detected using immunohistochemistry （IHC）. The expression levels of LDHA in vitro were also detected in the normal human proximal tubule epithelial cell line HK-2 and renal cell carcinoma cell lines A498， Caki-2， ACHN， and 786-O by using qRT-PCR and Western blot. A recombinant plasmid carrying LDHA-shRNA was constructed and then transfected into 786-O cells to down-regulate the expression of LDHA. Tumor proliferative capacity was monitored using CCK-8 assay， clonal formation assay and EdU assessments. Additionally， cell glycolytic activity was assessed through glucose uptake assay， lactate secretion assay， and ECAR analysis. ResultsIHC analysis revealed significantly higher expression of LDHA in RCC tissue compared to adjacent tissues（P<0.05）. Furthermore， RCC tissues with higher TNM stage exhibited greater expression of LDHA than those with lower TNM stage （P<0.05）. The results of qRT-PCR and Western blot demonstrated that the expression of LDHA in each RCC cell line was significantly higher than that in HK-2（P<0.05）. After blocking the expression of LDHA in 786-O， there was a significant down-regulation of cell proliferation and glycolysis capacity （P<0.05）. ConclusionsThe expression of LDHA in RCC tissue and RCC cell lines is significantly overexpressed compared with normal one， particularly in those with higher TNM stage. Knockdown of the expression of LDHA significantly suppresses cell proliferation and aerobic glycolysis capacity in 786-O.

Immunoexpression profile of hypoxia-inducible factor (HIF) targets in potentially malignant and malignant oral lesions: a pilot study

Abstract Oral potentially malignant disorders (OPMD) are associated with an increased risk of oral squamous cell carcinoma (OSCC). OSCC has an aggressive profile and is the most prevalent among different head and neck malignancies. Most OSCC patients are diagnosed with advanced stage tumors and have a poor prognosis. Cancer cells are able to reprogram their metabolism, even in the presence of oxygen, enhancing the conversion of glucose to lactate via the glycolytic pathway, a phenomenon mainly regulated by hypoxia-inducible factor (HIF) signaling. Thus, several glycometabolism-related biomarkers are upregulated. Objectives This study aimed to evaluate the immunoexpression of the HIF targets GLUT1, GLUT3, HK2, PFKL, PKM2, pPDH, LDHA, MCT4, and CAIX in OPMD and OSCC samples, in order to identify potential correlations between biomarkers' immunoexpression, clinicopathological features, and prognostic parameters. Methodology OSCC and OPMD samples from 21 and 34 patients (respectively) were retrospectively collected and stained for the different biomarkers by immunohistochemistry. Results CAIX and MCT4 expressions were significantly higher in OSCC samples when compared with OPMD samples, while the rest were also expressed by OPMD. GLUT3 and PKM2 alone, and the concomitant expression of more than four glycometabolism-related biomarkers were significantly correlated with the presence of dysplasia in OPMD. When considering OSCC cases, a trend toward increased expression of biomarkers and poor clinicopathological features was observed, and the differences regarding HK2, PFKL, LDHA and MCT4 expression were significant. Moreover, HK2 and CAIX were correlated with low survival rates. GLUT1 and GLUT3 were significantly associated with poor outcome when their expression was observed in the hypoxic region of malignant lesions. Conclusion OPMD and OSCC cells overexpress glycolysis-related proteins, which is associated with aggressive features and poor patient outcome. Further research is needed to deeply understand the glycolic phenotype in the process of oral carcinogenesis.

Identification of human LDHC4 as a potential target for anticancer drug discovery

One of the distinct hallmarks of cancer cells is aerobic glycolysis (Warburg effect). Lactate dehydrogenase A (LDHA) is thought to play a key role in aerobic glycolysis and has been extensively studied, while lactate dehydrogenase C (LDHC), an isoform of LDHA, has received much less attention. Here we showed that human LDHC was significantly expressed in lung cancer tissues, overexpression of Ldhc in mice could promote tumor growth, and knock-down of LDHC could inhibit the proliferation of lung cancer A549 cells. We solved the first crystal structure of human LDHC4 and found that the active-site loop of LDHC4 adopted a distinct conformation compared to LDHA4 and lactate dehydrogenase B4 (LDHB4). Moreover, we found that (ethylamino) (oxo)acetic acid shows about 10 times selective inhibition against LDHC4 over LDHA4 and LDHB4. Our studies suggest that LDHC4 is a potential target for anticancer drug discovery and (ethylamino) (oxo)acetic acid provides a good start to develop lead compounds for selective drugs targeting LDHC4.

Research Progress on Energy Metabolism and Radiosensitivity of Glioma / 肿瘤防治研究

Radiotherapy is an important auxiliary treatment for glioma. Although comprehensive treatment of glioma has made some progress in recent years, the prognosis is still poor. How to improve the radiosensitivity of glioma is one of the hot spots in current glioma research. The changes of energy metabolism in gliomas promote malignant progression and resistance to chemoradiotherapy, but the exact mechanism is still unclear. This paper reviews the research progress of energy metabolism in gliomas and its relation with radiosensitivity of gliomas, in order to lay a foundation for further exploration of improving radiosensitivity of gliomas.

Research progress of small molecule inhibitors that reverse tumor drug resistance by regulating tumor glucose metabolism / 中国临床药理学与治疗学

Tumor drug resistance is currently one of the most difficult clinical problems. There are many theories on the mechanism of tumor drug resistance, and metabolic reprogramming is one of its mechanisms. Tumor cells undergo metabolic reprogramming to meet the energy requirements of proliferation, especially the changes in the glucose metabolism. This article reviews the glucose metabolism reprogramming-related enzymes and the associated small molecule inhibitors that reverse tumor drug resistance.

Warburg effect of retinal energetic metabolism and its regulatory mechanism / 中华实验眼科杂志

Retinal metabolism includes material metabolism and energetic metabolism.Retina is one of the most energy-consuming nerve tissue in human body and mainly relies on glycolysis for energy production, which is similar to very fast-growing tumor tissue.This process is known as Warburg effect.Warburg effect is of great significance, which is demonstrated that glucose is metabolized via glycolysis in a more rapid approach in comparison with oxidative phosphorylation pathway.In addition, glucose also supplies neoplastic tissue with carbon source or metabolic intermediates due to biosynthesis.The produced energy of retina is a summation of different retinal cells and tissue, such as photoreceptors, retinal pigment epithelium (RPE), Müller cells and retinal capillary endothelial cells etc.To understand the underlying mechanism contributing to Warburg effect and provide insight into metabolic coupling between neuron and glia is of important significance.Since key glycolysis enzymes (HK2, PFKFB3 and PKM2) take a pivotal role in controlling retinal cell proliferation and neovascularization, bioenergetic strategy targeting these enzymes suggests new idea in the treatment of retinal diseases where energy failure is part of the pathogenesis.Investigating underlying mechanism of retinal energy metabolism can provide new ideas for the treatment of age-related macular degeneration (AMD) and other diseases related to disordered retinal energy metabolism.The Warburg effect of retinal energetic metabolism and its regulatory mechanism were reviewed in this article.

The reversed intra- and extracellular pH in tumors as a unified strategy to chemotherapeutic delivery using targeted nanocarriers

Solid tumors are complex entities, comprising a wide variety of malignancies with very different molecular alterations. Despite this, they share a set of characteristics known as "hallmarks of cancer" that can be used as common therapeutic targets. Thus, every tumor needs to change its metabolism in order to obtain the energy levels required for its high proliferative rates, and these adaptations lead to alterations in extra- and intracellular pH. These changes in pH are common to all solid tumors, and can be used either as therapeutic targets, blocking the cell proton transporters and reversing the pH changes, or as means to specifically deliver anticancer drugs. In this review we will describe how proton transport inhibitors in association with nanocarriers have been designed to block the pH changes that are needed for cancer cells to survive after their metabolic adaptations. We will also describe studies aiming to decrease intracellular pH in cancer using nanoparticles as molecular cages for protons which will be released upon UV or IR light exposure. Finally, we will comment on several studies that have used the extracellular pH in cancer for an enhanced cell internalization and tumor penetration of nanocarriers and a controlled drug delivery, describing how nanocarriers are being used to increase drug stability and specificity.

Role of glucose Warburg effect in Alzheimer's disease and targeted therapy of AMP-activated protein kinase / 中华神经医学杂志

Brain glucose metabolism disorder is one of the pathophysiological features of Alzheimer's disease (AD), in which aerobic glycolysis (Warburg effect) metabolic pathway abnormality is one of the causes of early cognitive impairment in AD, and improving brain energy metabolism has become an important strategy to prevent AD. AMP-activated protein kinase (AMPK) is a central hub regulating glucose metabolism, the most sensitive molecular compound for sensing fluctuations of energy levels in the body. Activation of AMPK can affect the Warburg effect and its key rate-limiting enzyme activity, regulate brain glucose metabolism involved in the pathogenesis of AD, to achieve the purpose of delaying AD progression and improving cognitive function in early clinical stage. In this review, we will discuss the pathogenesis of AD and targeting of AMPK from the perspective of Warburg effect in glucose metabolism.

Cell cannibalism in oral cancer: A sign of aggressiveness, de-evolution, and retroversion of multicellularity

Background: According to Darwin's theory of evolution, complex creatures evolve from more simplistic ancestors. Dollo's law of irreversibility states that evolution is irreversible. However, cancer cells tend to follow anti-Dollo's law. Unfavorable conditions such as hypoxia, acidic pH and low nutrients cause the cancer cells to switch their lifestyle atavistically in order to survive. They start behaving like a unicellular organism. There is a switch from normal metabolism to Warburg effect and finally cannibalism. Cannibalism is a cell eating cell phenomenon. It is defined as a large cell enclosing a smaller one within its cytoplasm and is known by odd names such as “bird's eye cells” or “signet ring cells.” Smaller tumor cells are found in the cytoplasm of larger tumor cells with crescent-shaped nucleus. Cannibalistic cells (CCs) are a feature of aggressive tumors. These cell types are vulnerable to metastasis. Aim: The aim of this study is to identify CCs in various histological grades of oral squamous cell carcinoma (OSCC) and to relate them with the pattern of invasion, lymphocytic response (LR), and mitotic figures (Mfs). The purpose of the article is to establish it as a marker of aggressiveness and metastasis and as an evidence of de-evolution and retroversion of multicellularity. Materials and Methods: Sixty-five histologically confirmed cases of OSCC were studied. Pattern of invasion, LR, number of CCs, and Mfs were recorded on 5 μ hematoxylin and eosin-stained tissue sections. ANOVA and t-test were applied; P < 0.05 was considered statistically significant. Results: CCs were more in sections with patchy LR, increased Mfs, and grade IV pattern of invasion. Conclusion: With increase in dedifferentiation, tumor cells start behaving like unicellular organisms with cell eating cell characteristics

Warburg Effects in Cancer and Normal Proliferating Cells: Two Tales of the Same Name / 基因组蛋白质组与生物信息学报·英文版

It has been observed that both cancer tissue cells and normal proliferating cells (NPCs) have the Warburg effect. Our goal here is to demonstrate that they do this for different reasons. To accomplish this, we have analyzed the transcriptomic data of over 7000 cancer and control tissues of 14 cancer types in TCGA and data of five NPC types in GEO. Our analyses reveal that NPCs accumulate large quantities of ATPs produced by the respiration process before starting the Warburg effect, to raise the intracellular pH from ∼6.8 to ∼7.2 and to prepare for cell division energetically. Once cell cycle starts, the cells start to rely on glycolysis for ATP generation followed by ATP hydrolysis and lactic acid release, to maintain the elevated intracellular pH as needed by cell division since together the three processes are pH neutral. The cells go back to the normal respiration-based ATP production once the cell division phase ends. In comparison, cancer cells have reached their intracellular pH at ∼7.4 from top down as multiple acid-loading transporters are up-regulated and most acid-extruding ones except for lactic acid exporters are repressed. Cancer cells use continuous glycolysis for ATP production as way to acidify the intracellular space since the lactic acid secretion is decoupled from glycolysis-based ATP generation and is pH balanced by increased expressions of acid-loading transporters. Co-expression analyses suggest that lactic acid secretion is regulated by external, non-pH related signals. Overall, our data strongly suggest that the two cell types have the Warburg effect for very different reasons.

Biological features of tumor associated fibroblasts and effect of Transwell co-culture on proliferation and metastasis of gastric cancer cells / 中国药理学通报

; Aim To culture primary human gastric cancer associated fibroblasts (CAFs) and normal fibroblasts (NFs), and to explore the biological characteristics and their effects on gastric cancer cells. Methods After isolation and culture of CAFs and NFs, growth curve was drawn by MTT. The a-smooth muscle actin (ot-SMA) and Vimentin were detected by Immunofluorescence, Western blot and qRT-PCR. MGC-803 cells were co-cultured with CAFs and NFs in Transwell suspension mode. The migration and invasion ability of gastric cancer cells was detected by Transwell. The proliferation activity and AMD3100 on CAFs-gastric cancer co-culture system were compared by MTT. The acidic property, lactic acid and ROS contents of co-culture system were determined by PH meter, lactic acid and DCFH-DA method. Results The morphology of CAFs, NFs cells were in long spindle or flat star shape. The proliferation ability and overlapping growth phenomenon of CAFs were higher than those of NFs. The expression of ct-SMA and Vimentin cells was positive in CAFs, but low or negative in NFs cells. The activity of gastric cancer in low density co-culture group > medium density group > high density group, the PH value of CAFs co-culture system decreased, the content of lactic acid and ROS was high, and only CAFs low density co-culture group had significant effect on promoting cancer. Conclusions The co-culture of gastric cancer cells with CAFs and NFs is greatly affected by the proportion. Low density co-culture can significantly improve the proliferation and metastasis ability of gastric cancer cells. High density co-culture may in turn inhibit the growth and metastasis of cancer cells, which may be related to the content of lactic acid and ROS.

Cancer Energy Metabolism: Shutting Power off Cancer Factory

In 1923, Dr. Warburg had observed that tumors acidified the Ringer solution when 13 mM glucose was added, which was identified as being due to lactate. When glucose is the only source of nutrient, it can serve for both biosynthesis and energy production. However, a series of studies revealed that the cancer cell consumes glucose for biosynthesis through fermentation, not for energy supply, under physiological conditions. Recently, a new observation was made that there is a metabolic symbiosis in which glycolytic and oxidative tumor cells mutually regulate their energy metabolism. Hypoxic cancer cells use glucose for glycolytic metabolism and release lactate which is used by oxygenated cancer cells. This study challenged the Warburg effect, because Warburg claimed that fermentation by irreversible damaging of mitochondria is a fundamental cause of cancer. However, recent studies revealed that mitochondria in cancer cell show active function of oxidative phosphorylation although TCA cycle is stalled. It was also shown that blocking cytosolic NADH production by aldehyde dehydrogenase inhibition, combined with oxidative phosphorylation inhibition, resulted in up to 80% decrease of ATP production, which resulted in a significant regression of tumor growth in the NSCLC model. This suggests a new theory that NADH production in the cytosol plays a key role of ATP production through the mitochondrial electron transport chain in cancer cells, while NADH production is mostly occupied inside mitochondria in normal cells.

Effects of tumor microenvironment on aerobic glycolysis of tumor cells / 实用肿瘤学杂志

The occurrence and development of tumor are closely related to abnormal cell metabolism.Tumor cells intake a large amount of glucose,and even with enough oxygen supply,they also generate energy primarily through the glycolysis pathway to meet the need of rapid growth.Tumor cell glycolysis is affected by many factors,and the tumor microenvironment is one of them.In re-cent years,there is evidence that immune/inflammatory factors such as transforming growth factor beta(TGF-β),tumor necrosis fac-tor alpha(TNF- α),interleukin-4(IL-4),and interleukin-6(IL-6)in the microenvironment matrix play a crucial role in the process of glucose metabolism,by regulating the aerobic glycolysis of energy and material to rapidly growth and proliferation of tumor cells.Therefore,the occurrence and development of tumor are focused on coming from the point of view of regulating the glycation of tumor cells with immune/inflammatory factors in the tumor microenvironment,providing new ideas for tumor control and clinical treat-ment.

Influence of STAT3 on promoting Warburg effect probably by upregula-ting GLUT2 expression in the malignant transformation of WB-F344 rat hepatic oval cells / 中国病理生理杂志

AIM:To investigate the influence of signal transducer and activator of transcription 3(STAT3)on Warburg effect in the malignant transformation of WB-F344 rat hepatic oval cells.METHODS:The WB-F344 cells were treated with N-methyl-N'-nitro-N-nitrosoguanidine(MNNG)and hydrogen peroxide(H2O2)to induce the malignant trans-formation.Evaluation of the transformed cells were measured by the soft agar colony formation assay and DNA aneuploidy with flow cytometry.The levels of glucose and lactate in the culture medium of the cells were detected by chromatography. The protein levels of alpha-fetoprotein(AFP),STAT3,p-STAT3 and glucose transporter 2(GLUT2)in the cells were ex-amined by Western blot analysis.The cell proliferation were evaluated by WST-1 assay,viable cell counting,measuring the S-phase fraction(SPF)and proliferation index(PI)using the data from flow cytometry analysis,and detecting proliferating cell nuclear antigen(PCNA)protein expression by Western blot.RESULTS:Compared with the control cells,the forma-tion of colonies in soft agar(P<0.05)and DNA aneuploidy(P<0.01)were elevated in transformed cells,and the ex-pression level of AFP was also augmented(P<0.05).The increases in the level of both glucose consumption(P<0.05) and lactate production(P<0.01)show that Warburg effect was enhanced in transformed cells.Meanwhile, the protein levels of GLUT2(P<0.01)and p-STAT3(P<0.01)in transformed cells were higher than those in the control cells.The cell proliferation parameters including SPF(P<0.01),PI(P<0.01), viable cell number and PCNA expression(P<0.01)in transformed cells were also elevated as compared with the control cells.Interestingly, stattic, an inhibitor of STAT3 activation,resulted in declines in glucose consumption(P<0.05)and lactate production(P<0.01)in the trans-formed cells.In addition,compared with transformed cells,formation of colonies in soft agar(P<0.01),DNA aneuploidy (P<0.01),AFP(P<0.05), GLUT2(P<0.05), and cell proliferation parameters including SPF(P<0.01), PI (P<0.01),viable cell number(P<0.05)and PCNA expression(P<0.05)were also decreased following stattic treat-ment in transformed cells.CONCLUSION:STAT3 promotes Warburg effect and cell proliferation probably by upregula-ting GLUT2 expression in the malignant transformation of hepatic oval cells.

Long time exposure to low concentrations of sodium arsenite induces Warburg effect in human bladder epithelial cells / 中华地方病学杂志

Objective To study the influence of long time exposure to low levels of sodium arsenite on Warburg effect in cultured human epithelial cells (SV-HUC-1) at different times.Methods SV-HUC-1 cells were exposed to 0.5 μmol/L sodium arsenite for 10,20,30 weeks and cells cultured without sodium arsenite for 10,20,30 weeks were regarded as control groupsin vitro.Lactate assay kit and glucose assay kit were used to measure the lactate secretion and glucose consumption levels,and cells mRNA and protein expressions of SCL2A1 and hexokinase2(HK2) were detected using Real-time PCR and Western blotting.Results The levels of lactate secretion [(4.67 ± 0.20),(7.47 ± 0.28),(12.46 + 0.47) mmol/L],glucose consumption [(2.86 ± 0.11),(4.25 ± 0.19),(6.38 ± 0.05) mmol/L] and expression of HK2 protein (1.21 ± 0.06,1.36 ± 0.13,1.60 ± 0.12) increased significantly after treated with 0.5 μmol/L sodium for 10,20,30 weeks compared with those of control groups [(3.04 ± 0.11),(3.90 ± 0.32),(4.77 ± 0.24) mmol/L;(2.17 ± 0.15),(2.48 ± 0.24),(2.71 ± 0.13) mmol/L;1.00 ± 0.00;P ＜ 0.05].Compared with control group,the expressions of SCL2A1 mRNA,HK2 mRNA and SCL2A1 protein in SV-HUC-1 cells treated with sodium arsenite for 10 weeks increased but the difference was not statistically significant (P ＞ 0.05).While the expressions of SCL2A1 mRNA,HK2 mRNA and SCL2A1 protein in SV-HUC-1 cells treated with sodium arsenite for 20 and 30 weeks increased significantly compared to those of control groups (P ＜ 0.05).Conclusion Long-term exposure to low concentrations of sodium arsenite can increase glycolysis in SV-HUC-1 and induce Warburg effect.

Radiosensitization of irisquinone on the Warburg effect of MDA-MB231 cells / 中华放射医学与防护杂志

Objective To study the radiosensitization of irisquinone on the Warburg effect of MDA-MB231 cells.Methods MDA-MB231 cells in the exponential growth phase were divided into 6 groups:control group,irisquinone group,radiation group,irisquinone plus radiation group(Irisquinone + RA),negative control group,and experimental group (siRNA).Colony formation assay was used to measure cell survival fraction of MDA-MB231 cells.Single-hit multi-target model was used to fit the survival curve and calculate the sensitive enhancement ratio (SER).Flow cytometry was used to measure cell apoptosis.The relative expression levels of HK Ⅱ mRNA and protein in each group were detected by qRT-PCR and Western blot respectively.Results The values of D0,Dq and SF2 in the irisquinone plus radiation group were obviously lower than those in the radiation group.The SER of irisquinone was 1.52.Compared with the other groups,the cell apoptosis rate was increased (t =13.29,12.09,5.90,3.83,P ＜ 0.05),while the relative expression levels of HK Ⅱ mRNA (t =9.14,10.48,3.40,P＜0.05) and protein (t=13.39,16.08,5.81,P ＜ 0.05) were decreased in the irisquinone plus radiation group significantly.Conclusions Radiosensitization function of irisquinone inhibits the Warburg effect of MDA-MB231 cells by down-regulating the expression of HK Ⅱ.

Metabolic Interplay between Tumour Cells and Cancer-Associated Fibroblasts (CAFs) under Hypoxia versus Normoxia

The growth of tumour cells is closely related to cancer-associated fibroblasts (CAFs)present within their microenvironment. CAFs, the most abundant cells in tumour stroma, secretegrowth factors that play pivotal roles in tumour cell proliferation, metabolism, angiogenesis andmetastasis. Tumour cells adapt to rapid environmental changes from normoxia to hypoxia throughmetabolic interplay with CAFs. In this mini review, we discuss the role of lactate dehydrogenases(LDHs) and monocarboxylate transporters (MCTs) on the metabolic interplay between tumourcells and CAFs under hypoxia compared to normoxia. The LDHs catalyse the interchange oflactate and pyruvate, whereas MCTs facilitate the influx and efflux of monocarboxylates, especiallylactate and pyruvate. To sum up, tumour cells switch their metabolic state between glycolysis andoxidative phosphorylation through metabolic interplay with CAFs, which exhibit the Warburgeffect under hypoxia and reverse Warburg effect under normoxia.