JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2018
·Vol. 22
·期 5
·2774-2790
·
IF 4.302
Qiongli Su,Ting Tao,Lei Tang,Jun Deng,Kwame Oteng Darko,Sichun Zhou,Mei Peng,Shanping He,Qing Zeng,Alex F. Chen,Xiaoping Yang
Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels that are correlated with the sensitivity of anticancer chemotherapeutic drugs. THP is one of the major drugs used in non-muscle-invasive bladder cancer instillation chemotherapy. However, low response ratio of THP (19.7%) treatment to human genitourinary tumours using collagen gel matrix has been observed. This study aims to investigate the effect of down-regulation of PKM2 on THP efficiency. Via inhibitor or siRNA, the effects of reduced PKM2 on the efficiency of THP were determined in 2 human and 1 murine bladder cancer cell lines, using MTT, cologenic and fluorescence approaches. Molecular mechanisms of PKM2 on THP sensitization were explored by probing p-AMPK and p-STAT3 levels via WB. Syngeneic orthotopic bladder tumour model was applied to evaluate this efficiency in vivo, analysed by Kaplan-Meier survival curves, body and bladder weights plus immunohistochemistric tumour biomarkers. PKM2 was overexpressed in bladder cancer cells and tissues, and down-regulation of PKM2 enhanced the sensitivity of THP in vitro. Activation of AMPK is essential for THP to exert anti-bladder cancer activities. On the other hand, down-regulating PKM2 activates AMPK and inhibits STAT3, correlated with THP sensitivity. Compared with THP alone (400 μmol L −1 , 50 μL), the combination with metformin (60 mmol L −1 , 50 μL) stopped growth of bladder cancer completely in vivo (combination group VS normal group P = .078). Down-regulating the expression of PKM2 enhances the anticancer efficiency of THP. This study provides a new insight for improving the chemotherapeutic effect of THP.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2020
·Vol. 20
·期 6
·1-1
·
IF 1.785
Zhirong Zhu,Guiliang Tang,Jiajun Yan
Prostate cancer (PCa), an epithelial malignancy that occurs in the prostate, is the second leading cause of cancer death worldwide. MicroRNAs (miRs/miRNAs) are reported to have important applications in the field of cancer diagnosis and treatment. The present study aimed to investigate the function of miRNA‑122 in the chemoresistance of PCa cells and the underlying mechanism. Significantly decreased miR‑122 and increased pyruvate kinase (PKM2) levels were observed in docetaxel‑resistant PCa cells, and PKM2 was negatively correlated with miR‑122. MiR‑122 mimic transfection in docetaxel‑resistant LNCaP cells significantly inhibited cell proliferation, promoted apoptosis and decreased glucose uptake and lactate production, which was counteracted by PKM2 overexpression. Inhibition of miR‑122 in LNCaP cells had an opposite effect to miR‑122 mimic transfection. In addition, miR‑122 mimic transfection significantly increased the sensitivity of docetaxel‑resistant LNCaP cells to docetaxel, while inhibition of miR‑122 significantly decreased the sensitivity of LNCaP cells to docetaxel. Luciferase reporter assays showed that miR‑122 regulated PKM2 expression by binding to the 3'‑untranslated region of PKM2. The results suggest that upregulation of miR‑122 could enhance docetaxel sensitivity, inhibit cell proliferation and promote apoptosis in PCa cells,possibly through the downregulation of its target protein PKM2.
研究领域:
肿瘤学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Stem Cell Research & Therapy
·
2025
·Vol. 16
·期 1
·1-21
·
IF 7.3
Zhu Yanlin,Yang Yuhan,Lan Yuyan,Yang Zun,Gao Xiang,Zhou Jie
Background Diabetes mellitus (DM) and periodontitis have a bidirectional relationship, with each being a high-risk factor for the other. Prolonged hyperglycemia exacerbates periodontal inflammation and disrupts bone homeostasis. Pyruvate kinase M2 (PKM2), a key enzyme in glycolysis, is involved in metabolic reprogramming, but its role in osteogenesis under high-glucose (HG) inflammatory conditions remains largely unknown. This study aimed to investigate the effects of HG and inflammation on bone marrow mesenchymal stem cells (BMSCs) under indirect co-culture conditions and to explore how PKM2 regulates metabolism and mitochondrial function during osteogenic differentiation in HG inflammatory environments, elucidating its role in diabetic periodontitis (DP).Methods Expose BMSCs to conditioned medium (CM) collected from RAW264.7 cells stimulated with HG and/or lipopolysaccharide (LPS). BMSCs functionality was assessed using CCK8, EdU, Annexin V-PI apoptosis assay, alkaline phosphatase (ALP), and Alizarin Red S (ARS) staining. Metabolic characteristics were evaluated through Seahorse assays, lactate production, glucose uptake, and ATP measurements. Mitochondrial function was assessed via JC-1, and ROS staining, Mito-Tracker staining, and transmission electron microscopy (TEM). Gene and protein expression were analyzed by quantitative real-time PCR and western blotting. In vivo therapeutic effects of shikonin were validated via micro-CT and histological staining in a diabetic periodontitis mouse model.Results In vitro experiments demonstrated that HG inflammatory conditions impaired the survival of BMSCs, suppressed osteogenic differentiation, and induced metabolic reprogramming. This reprogramming was characterized by enhanced glycolysis, impaired oxidative phosphorylation (OXPHOS), abnormal upregulation of PKM2 expression, and mitochondrial dysfunction accompanied by morphological alterations. Shikonin effectively reversed these adverse effects by inhibiting PKM2 tetramerization, rescuing the loss of osteogenic function in BMSCs. The therapeutic potential of shikonin was confirmed in the diabetic periodontitis mouse model.Conclusion PKM2 impairs the osteogenesis of BMSCs by affecting metabolism and mitochondrial function, suggesting it as a potential therapeutic target for diabetic periodontitis.
研究领域:
细胞生物学
·
代谢组学
·
口腔医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
·
2020
·
IF 6.992
Shan Lu,Yu Tian,Yun Luo,Xudong Xu,Wenxiu Ge,Guibo Sun,Xiaobo Sun
Introduction Inflammation is a key factor in myocardial ischemia/reperfusion (MI/R) injury. Targeting leucocyte-mediated inflammation is an important strategy for MI/R therapy. Iminostilbene (ISB), a simple dibenzoazepine small molecule compound, has a strong anti-neurodegenerative effect. However, no study has shown the cardioprotective effect of ISB. Objectives This study aimed to investigate the role of ISB against MI/R injury and identify its molecular target. Methods To verify the cardiac protection of ISB in vivo and in vitro , we performed rat MI/R surgery and subjected inflammatory modeling of macrophages. In terms of molecular mechanisms, we designed and synthesized a small molecular probe of ISB and employed it on the click chemistry-activity-based protein profiling technique to fish for ISB targets in macrophages. To identify the target, we applied the competitive inhibition assay, surface-plasmon resonance (SPR), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assay. Results In vivo , ISB showed robust anti-myocardial injury activity by improving cardiac function, reducing myocardial infarction, and inhibiting macrophage-mediated inflammation. In vitro , ISB strongly inhibited the transcription and the expression levels of inflammatory cytokines in macrophages. The pyruvate kinase isozyme type M2 (PKM2) was identified as the potential target of ISB through proteomic analysis and the competitive assay was performed for specific binding verification. Further thermodynamic and kinetic experiments showed that ISB was bound to PKM2 in a dose-dependent manner. Moreover, in terms of the biological function of ISB on PKM2, ISB reduced the expression of PKM2, thereby reducing the expression of HIF1α and the phosphorylation of STAT3. Conclusion This study for the first time demonstrated that ISB targeted PKM2 to reduce macrophage inflammation thereby significantly alleviating MI/R injury.
研究领域:
心脏病学
·
药理学
·
炎症研究
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2024
·
IF 4
Chengmeng Jin,Wei Hu,Yuqi Wang,Hao Wu,Siying Zeng,Minfeng Ying,Xun Hu
Most cancer cells exhibit high glycolysis rates under conditions of abundant oxygen. Maintaining a stable glycolytic rate is critical for cancer cell growth as it ensures sufficient conversion of glucose carbons to energy, biosynthesis, and redox balance. Here we deciphered the interaction between PKM2 and the thermodynamic properties of the glycolytic pathway. Knocking down or knocking out PKM2 induced a thermodynamic equilibration in the glycolytic pathway, characterized by the reciprocal changes of the Gibbs free energy (ΔG) of the reactions catalyzed by PFK1 and PK, leading to a less exergonic PFK1-catalyzed reaction and a more exergonic PK-catalyzed reaction. The changes of the ΔGs of the two reactions causes the accumulation of intermediates, including the substrate PEP (the substrate of PK), in the segment between PFK1 and PK. The increased concentration of PEP in turn increased PK activity in the glycolytic pathway. Thus, the interaction between PKM2 and the thermodynamic properties of the glycolytic pathway maintains the reciprocal relationship between PK concentration and its substrate PEP concentration, by which, PK activity in the glycolytic pathway can be stabilized and effectively counteracts the effect of PKM2 KD or KO on glycolytic rate. In line with our previous reports, this study further validates the roles of the thermodynamics of the glycolytic pathway in stabilizing glycolysis in cancer cells. Deciphering the interaction between glycolytic enzymes and the thermodynamics of the glycolytic pathway will promote a better understanding of the flux control of glycolysis in cancer cells.
研究领域:
癌症生物学
·
代谢途径
·
热力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2023
·Vol. 50
·期 7
·561-572
·
IF 2.9
Yawei He,Wanjing Chen,Liang Yu,Yanwei Liu,Yunsheng Cheng,Xianghua Li,Gang Yu
Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the β-catenin, c-Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/β-catenin pathway.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
·
转录调控
·
代谢途径
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 6
·2804
·
IF 4.9
Danni Chen,Opeyemi B. Fasina,Jiahui Lin,Jiayuan Zeng,Majid Manzoor,Hiroshi Ohno,Lan Xiang,Jianhua Qi
In previous studies, we isolated a series of novel gentisides with nerve growth factor (NGF)-mimic activities fromGentiana rigescensFranch and conducted continuous structure–activity relationship (SAR) studies. Recently, a lead compound named TBG096 was discovered with significant NGF-mimic activity, low toxicity, and ability to pass through the blood–brain barrier (BBB). At the cell level, TBG096 exerts NGF-mimic activity by regulation of heat-shock cognate protein 70 (Hsc70) and downstream proteins. Subsequently, high-fat diet (HFD)-induced Alzheimer disease (AD) mouse models were used to evaluate the anti-AD efficacy of the compound. TBG096 significantly improved the memory dysfunction of AD mice at doses of 0.1, 5, and 20 mg/kg, respectively. In order to elucidate the mechanism of action of the compound against AD, the RNA-sequence analysis of transcriptomics, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining, and Western blot analysis were performed using animal samples. TBG096 significantly increased the expression of the Wnt gene family (Wnt10b,Wnt5a, andWnt1) and the number of mature neurons and newborn neurons in the hippocampus and cerebral cortex of AD mice, respectively. At the same time, it reduced the activity of microglia, astrocyte cells, and expression of inducible nitric oxide synthase (INOS) in the brain. Moreover, this compound significantly increased phosphorylated-adenosine 5′-monophosphate-activated protein kinase (AMPK), Hsc70, and lysosomal-associated membrane protein 2a (LAMP2A) and decreased the expression of hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), amyloid precursor protein (APP), microtubule-associated protein tau (Tau), phosphoryl-Tau, and β-amyloid (Aβ) at the protein level. These results suggest that TBG096 produced the NGF-mimic activity and the anti-AD effect via promoting neurogenesis and modification of the Hsc70/HK2/PKM2/LAMP2A signaling pathway, proposing a potential novel approach to counteracting cognitive decline by developing small molecules that promote neurogenesis and the Hsc70 signaling pathway.
研究领域:
药理学
·
神经科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Xiuhuan Jiang,Guoying Miao,Na Shen,Qingxia Han,Xiaoru Han,Zichang Qiao,Kexin Feng,Zhuo Tan,Yaguang Wang,Xiuhua Liu,Chen Wu,Zhenzhen Yan
Metabolic reprogramming toward aerobic glycolysis is increasingly recognized as a key mechanism in the pathogenesis of psoriasis, but the underlying regulatory mechanisms remain unclear. Here, we identify Toll‐interacting protein (TOLLIP) as a critical regulator of psoriasis pathogenesis through its modulation of glycolytic metabolism. We found that TOLLIP is significantly upregulated in psoriatic lesions, and its genetic deletion in mice exacerbated disease severity in imiquimod (IMQ)‐induced psoriasis models. Mechanistically, TOLLIP interacts with the rate‐limiting glycolytic enzyme pyruvate kinase M2 (PKM2) via its coupling of ubiquitin to ER degradation (CUE) domain (179–274 aa), inhibits PKM2's metabolic enzyme activity and attenuates aerobic glycolysis, thereby mitigating keratinocyte hyperproliferation and inflammation. Therapeutic delivery of Tollip or Tollip (179–274 aa) via adeno‐associated virus (AAV) vectors ameliorated psoriasis progression in mice. Our findings establish the TOLLIP‐PKM2‐glycolysis axis as a key mechanism linking metabolic reprogramming to psoriasis pathogenesis, and propose TOLLIP as a promising therapeutic target. In this study, we identify TOLLIP as a critical regulator of psoriasis pathogenesis through its modulation of glycolytic metabolism. Our findings establish the TOLLIP‐PKM2‐glycolysis axis as a key mechanism linking metabolic reprogramming to psoriasis pathogenesis, and propose TOLLIP as a promising therapeutic target.
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Bing Li,Pei-rong Gan,Jing Pang,Jian-jian Li,Hong Wu
Glycolytic reprogramming-driven aberrant proliferation of FLSs is a major cause of synovial hyperplasia in rheumatoid arthritis (RA). Geniposide (GE), an iridoid glycoside extracted from the plant Gardenia jasminoides J. Ellis, has been confirmed to inhibit the proliferative activity of RA-FLSs. However, whether this effect involves the regulation of glycolytic metabolism remains unclear. In this study, collagen-induced arthritis (CIA) rat models and TNF-α-induced MH7A cell models were established to investigate the specific mechanism by which GE regulates glycolytic reprogramming. The results showed that GE not only ameliorated synovial hyperplasia and suppressed glycolysis in CIA rats, but reduced the abnormal proliferation and glycolytic levels of TNF-α-induced MH7A cells. Increased lactylation of PKM2 was observed in the synovium of CIA rats and in TNF-α-induced MH7A cells, accompanied by the transition of PKM2 from tetramer to dimer and enhanced nuclear translocation. GE was found to inhibit the lactylation of PKM2. The SphK1/p300 signaling axis was activated both in vivo and in vitro . Investigations revealed that PF543, an inhibitor of SphK1, and A-485, an inhibitor of p300, inhibited the lactylation of PKM2. Moreover, GE suppressed the SphK1/p300 axis and prevented the interaction between PKM2 and p300. The inhibitory effect of GE on glycolysis was attenuated by lactate and the p300 agonist Cholera Toxin B (CTB). It was also found the suppression of glycolysis by GE was counteracted by both lactate and CTB. These results suggested GE suppressed the abnormal proliferation of FLSs by inhibiting the SphK1/p300-mediated lactylation of PKM2, highlighting a novel treatment strategy for RA.
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Ziwei Kang,Ruoyan Xie,Yiming Cui,Zhiwei Chen,Jincheng Li,Jinyu Lv,Weijia Ye,Peixin Zhao,Keke Zhang,Jian Hong,Hengdong Qu
Introduction:: Pyruvate kinase M2 (PKM2), the rate-limiting enzyme of glycolysis, plays a critical role in macrophage activation and a broad spectrum of chronic liver diseases. However, whether PKM2 contributes to the pathogenesis of acute liver injury (ALI) remains largely unexplored.Methods: PKM2 expression was assessed in human and mouse ALI livers. Macrophage-specific PKM2 knockout mice were challenged by two independent ALI models, induced by acetaminophen (APAP) and lipopolysaccharide/D-galactosamine (LPS/D-GalN), to explore the role and regulatory mechanism of macrophage PKM2 in ALI progression.Results: By bioinformatic screening and analysis of ALI liver, we found that PKM2 was significantly upregulated in the liver tissues of ALI patients and mice. Immunofluorescence staining further demonstrated that PKM2 was markedly upregulated in macrophages during ALI progression. Notably, macrophage PKM2 depletion effectively alleviated APAP- and LPS/D-GalN-induced ALI, as demonstrated by ameliorated immune cells infiltration, pro-inflammatory mediators, and hepatocellular cell death. PKM2-deficient macrophages showed M2 anti-inflammatory polarization in vivo and in vitro. Furthermore, PKM2 deletion limited HIF-1α signaling and aerobic glycolysis of macrophages, which thereby attenuated macrophage pro-inflammatory activation and hepatocyte injury. Pharmacological PKM2 antagonist efficiently ameliorated liver injury and prolonged the survival of mice in APAP-induced ALI model.Discussion:: Our study highlights the pivotal role of macrophage PKM2 in advancing ALI, and therapeutic targeting of PKM2 may serve as a novel strategy to combat ALI.
研究领域:
医学
·
免疫学
·
肝脏病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Qianrang Lu,Meiching Ong,Xuewen Yi,Muqiong Xing,Xinyao Tian,Ke Zhang,Ling Lu,Hao Wang,Xiaohan Lin,Jun Fang,Aibo Mu,Jiaying Cao,Jingyu Jiang,Feng Gao,Hongjun Li,Baohong Wang,Qi Ling
Macrophages are central mediators of hepatic inflammation and fibrosis in metabolic-associated steatohepatitis (MASH), yet the mechanisms driving their activation remain unclear. Integration of four human single-nucleus transcriptomic datasets identified Coagulation Factor XIII-A (F13A1)-positive macrophages as the predominant subset in MASH livers, a finding validated in patient samples and murine models. Lipid-stressed hepatocytes induce F13A1 expression through a sphingosine-1-phosphate (S1P)-dependent mechanism. Silencing F13A1 suppressed the pro-inflammatory phenotype and alleviated hepatic injury in vivo. Mechanistically, F13A1 directly interacted with pyruvate kinase M2 (PKM2), promoting its dimerization, a process enhanced by intracellular calcium levels. Dimerized PKM2 translocated into the nucleus and upregulates interleukin-1 beta (IL1B) expression via the PKM2/HIF1A (Hypoxia-inducible factor 1-alpha) axis. In addition, F13A1 enhanced the Warburg effect in macrophages through PKM2-mediated metabolic reprogramming. Pharmacologic activation of PKM2 with DASA-58 abrogated F13A1-driven inflammation, and PEG-PLA micelle-mediated delivery of DASA-58 ameliorated hepatic inflammation in vivo. These findings establish F13A1 as a critical driver of macrophage-mediated inflammation in MASH and highlight the F13A1/PKM2/HIF1A pathway as a promising therapeutic target.
✓ 已验证
DOI
高影响因子
MOLECULAR CELL
·
2020
·
IF 15.584
Pei-pei Hou,Li-juan Luo,Hang-zi Chen,Qi-tao Chen,Xue-li Bian,Sheng-fu Wu,Jia-xin Zhou,Wen-xiu Zhao,Jian-ming Liu,Xiao-min Wang,Zhi-yuan Zhang,Lu-ming Yao,Qinghua Chen,Dawang Zhou,Qiao Wu
Summary Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.
研究领域:
肿瘤学
·
免疫学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）