丙酮酸脱氢酶与肿瘤

丙酮酸脱氢酶是丙酮酸生成乙酰辅酶A的关键酶,而乙酰辅酶A是葡萄糖进入三羧酸循环有氧氧化的首要原料。丙酮酸脱氢酶激酶可以抑制丙酮酸脱氢酶的活性。肿瘤细胞的总体丙酮酸脱氢酶激酶表达增加,造成丙酮酸脱氢酶活性降低,导致肿瘤细胞主要通过糖酵解的方式获取能量。恶性肿瘤糖酵解活跃能促进细胞增殖和抑制细胞凋亡,而形成肿瘤细胞糖酵解的微环境可保护肿瘤细胞逃避宿主免疫杀伤并减轻化疗药物损伤,还有利于肿瘤细胞的侵袭和转移。因此,丙酮酸脱氢酶在肿瘤的发生发展过程中起作用。事实上胚胎干细胞以及成体干细胞也主要是以糖酵解的方式获取能量。由此推断,丙酮酸脱氢酶的活性可能与肿瘤细胞的干性相关。     

M2型丙酮酸激酶在肿瘤代谢中的作用

M2型丙酮酸激酶（PKM2）是糖酵解途径的一个关键限速酶,在多种恶性肿瘤细胞中高表达.在肿瘤糖代谢通路中,PKM2可以通过在高活性的四聚体和低活性的二聚体之间相互转化,促进肿瘤的糖酵解和细胞增殖.肿瘤细胞通过多种方式调节PKM2的表达和酶活性如转录调节、变构调节和翻译后修饰调节.PKM2在肿瘤发生和肿瘤代谢中的重要作用使它有望成为肿瘤治疗的新靶点.     

肿瘤细胞的异常糖代谢

肿瘤细胞糖代谢异常与多种机制有关,如缺氧诱导因子（HIF）的参与可激活糖酵解相关酶类,有利于肿瘤细胞采取糖酵解方式获能;线粒体功能低下或数量减少可一定程度抑制葡萄糖氧化磷酸化途径;某些癌基因的激活及抑癌基因的失活也参与调节线粒体氧化呼吸链及糖酵解相关酶类,从而影响糖代谢过程;肿瘤细胞氧化磷酸化的相关酶类合成受到抑制等。此外,糖代谢异常对肿瘤细胞的生长、侵袭和转移具有重要作用。     

Akt及其在肿瘤细胞糖酵解中的作用

Akt通过对葡萄糖转运子、己糖激酶和柠檬酸裂解酶等因子的作用,达到增强肿瘤细胞糖酵解的效应.Akt在肿瘤细胞中的异常升高对肿瘤细胞糖代谢产生影响,继而对肿瘤细胞的生存能力、增殖能力、抗凋亡等有一定作用.抑制Akt磷酸化水平可抑制癌细胞生长.因此,Akt可作为肿瘤临床治疗的新靶点.     

microRNAs调控自噬研究进展

microRNAs是真核生物中内源性表达的非编码RNA，长约18~25个核苷酸。成熟的microRNAs通过碱基互补配对与靶基因3'UTR区域结合降解目标mRNA或抑制其翻译来调控基因的表达水平，是一种对基因表达的转录后调控方式。研究表明，microRNAs在细胞的增殖、分化及死亡等生理病理过程中均具有调控作用，本文将对其在Ⅱ型程序性细胞死亡即自噬过程中的作用进行综述。      

M2型丙酮酸激酶非代谢功能在肿瘤治疗中的研究进展

丙酮酸激酶(pyruvate kinase,PK),作为糖酵解的关键酶之一,可以编码四个不同亚型的基因,其中M2型丙酮酸激酶(PKM2)主要表达在正常人类胚胎发育中,和组织修复、再生密切相关,随着研究的深入,PKM2在肿瘤组织中的作用受到越来越多的关注。PKM2除了代谢作用外,还可以通过PKM2抑制剂和激活剂变构调节四聚体和二聚体,二聚体状态的PKM2可以调节细胞核中的基因表达及细胞增殖。本文综述了PKM2表达调控,重点介绍了PKM2非代谢功能及在抗肿瘤治疗中的临床应用。     

M2型丙酮酸激酶与Warburg效应在肺癌中的研究进展

靶向肿瘤代谢途径是肺癌治疗的新兴策略之一。Warburg效应是肿瘤代谢的主要特征,表现为肿瘤细胞在有氧条件下通过糖酵解获得能量。最近研究表明,M2型丙酮酸激酶作为糖酵解途径关键酶的异常表达与肺癌的增殖、转移、诊断、治疗及预后密切相关,是肺癌治疗的潜在靶点。     

卵巢癌组织中miR-125B-5p通过调控己糖激酶-2降低肿瘤能量代谢和抑制肿瘤细胞增殖

背景与目的 细胞内能量代谢异常是肿瘤的十大特征之一,微小RNA(microRNA,miRNA)可能通过调节有氧糖酵解相关酶的表达来介导有氧糖酵解,从而调控肿瘤细胞代谢和增殖.本研究对卵巢癌患者肿瘤组织中miR-125B-5p和己糖激酶-2(hexokinase-2,HK2)的表达水平与肿瘤能量代谢和增殖的关系进行了初步...     

细胞微环境microRNAs在肿瘤侵袭转移中的作用

肿瘤微环境是肿瘤发生、发展的重要组成成分，微环境中microRNAs作为原癌基因或抑癌基因能够进入靶细胞，调控相关靶基因的表达和功能，从而影响微环境的构成，并在肿瘤细胞侵袭和转移中发挥重要作用。因此，microRNAs在肿瘤诊断治疗中具有诱人的应用前景。     

丙酮酸激酶M2型在肿瘤发生过程中的作用

人丙酮酸激酶(PK)有M1、M2、R和L等4种同工酶.其中M2型主要在早期胚胎组织中表达,胎儿出生后逐渐被其他3种同工酶取代,但在成体干细胞中人丙酮酸激酶也有表达.几乎所有的肿瘤细胞都存在M2型表达,并同各种内源性、外源性癌蛋白及增殖调节因子相互作用以增强肿瘤细胞的增殖,因此被称为肿瘤特异性丙酮酸激酶.     

Isotype-specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation

Tumor cells express the glycolytic regulator pyruvate kinase subtype M2 (M2-PK), which can occur in a tetrameric form with high affinity to its substrate phosphoenolpyruvate (PEP) and a dimeric form with a low PEP affinity. The transition between both conformations contributes to the control of glycolysis and is important for tumor cell proliferation and survival. Here we targeted M2-PK by synthetic peptide aptamers, which specifically bind to M2-PK and shift the isoenzyme into its low affinity dimeric conformation. The aptamer-induced dimerization and inactivation of M2-PK led to a significant decrease in the PK mass-action ratio as well as ATP:ADP ratio in the target cells. Furthermore, the expression of M2-PK-binding peptide aptamers moderately reduced the growth of immortalized NIH3T3 cell populations by decelerating cell proliferation, but without affecting apoptotic cell death. Moreover, the M2-PK-binding peptide aptamers also reduced the proliferation rate of human U-2 OS osteosarcoma cells. In the present study, we developed the first specific inhibitors of the pyruvate kinase isoenzyme type M2 and present evidence that these inhibitors moderately decelerate tumor cell proliferation.     

Identification of a glycolysis-related gene signature for predicting pancreatic cancer survival

BackgroundPancreatic cancer (PC) is one of the most common malignant tumors of the digestive tract. Its clinical symptoms are obscure and atypical. It is difficult to diagnose and treat. Tumor cells mainly obtain energy through glycolysis to promote their growth. Inhibiting glycolysis can inhibit proliferation and kill tumor cells.MethodsUsing bioinformatics method, we investigate the relationships between glycolysis-related genes and PC tumor samples’ epidemiologic information comprehensively.ResultsDifferent expression levels of 27 genes were identified. Using bioinformatics methods, we plotted two subgroup curves based on glycolysis-related gene expression level. Potential predictive genes were screened and their prognostic values were analyzed. Survival among high-risk group and low risk group had significant difference. Receiver operating characteristic (ROC) curve analysis indicated that area under curve (AUC) of 10 genes was greater than 0.8. These genes could be used for clinical diagnosis and prediction for PC. Two potential predictors [Kinesin Family Member 20A (KIF20A) and MET Proto-Oncogene, Receptor Tyrosine Kinase (MET)] that met the independent predictive value were selected. In univariate analysis, we screened out 3 regulators MET, protein kinase CAMP-activated catalytic subunit alpha (PRKACA) and KIF20A. According to the 3 regulatory factors, the prognostic signals of PC were constructed, by which the samples with good prognosis and poor prognosis can be clearly distinguished independently of potential confounding factors.ConclusionsOur results indicate that for PC, glycolysis -related genes could be promising therapeutic targets or prognostic indicators.     

紫草素调节有氧糖酵解代谢诱导急性淋巴细胞白血病细胞凋亡

目的:探讨紫草素通过调节白血病细胞能量代谢影响细胞增殖与凋亡的具体机制。方法:采用MTS法检测细胞增殖，流式细胞术检测细胞凋亡；采用Western blotting 法检测细胞凋亡相关蛋白的表达，包括cleaved-caspase 8、cleaved-PARP、cleaved-caspase 3。利用丙酮酸激酶（PK）活性检测试剂盒评估紫草素对PK酶活性的影响；利用海马能量代谢检测仪检测Reh细胞经紫草素处理后其有氧糖酵解代谢水平的变化。结果:紫草素以时间剂量依赖性的方式抑制白血病细胞增殖，并诱导白血病细胞凋亡，凋亡率与药物剂量呈正相关关系（P＜0.01）。紫草素激活caspase级联反应，凋亡相关蛋白cleaved-caspase 8、cleaved-PARP及cleaved-caspase 3的表达随紫草素的剂量增加而增加。紫草素抑制白血病细胞PK酶的活性，并抑制有氧糖酵解代谢的代偿能力（P＜0.001）。结论:紫草素抑制急性淋巴细胞白血病Reh细胞有氧糖酵解代谢的代偿能力，并诱导Reh细胞以caspase依赖性的方式凋亡。     

Neuromedin U regulates the anti-tumor activity of CD8+ T cells and glycolysis of tumor cells in the tumor microenvironment of pancreatic ductal adenocarcinoma in an NMUR1-dependent manner

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis, which is lethal in approximately 90% of cases despite advanced standard therapies. A typical feature of PDAC is the immunosuppressive tumor microenvironment with multiple immunosuppressive factors including neurotransmitters. Recently, neuromedin U (NMU), a highly conserved neuropeptide with many physiological functions, has attracted attention for its roles in tumorigenesis and metastasis in several types of cancers. However, whether NMU affects PDAC progression remains unclear. In this study, using an orthotopic mouse model of PDAC in combination with bioinformatics analysis, we found that NMU was upregulated in tumor tissues from the patients with PDAC and positively correlated with a poor prognosis of the disease. Interestingly, knockout of the Nmu gene in mice enhanced the anti-tumor functions of tumor-infiltrating CD8⁺ T cells in an NMU receptor 1-dependent manner. Additionally, NMU promoted the glycolytic metabolism of mouse PDAC tumors. The activities of pyruvate kinase (PK) and lactate dehydrogenase (LDH), pivotal enzymes involved in the regulation of lactate production, were markedly reduced in tumor tissues from NMU-knockout mice. In vitro the presence of LDHA inhibitor can reduce the production of lactic acid stimulated by NMU, which can increase the anti-tumor activity of CD8⁺ T cells. Moreover, treatment of the pancreatic cancer cells with a phosphoinositide 3-kinase (PI3K) inhibitor diminished NMU-induced lactate production and the activities of PK and LDH, suggesting that NMU might regulate glycolysis via the PI3K/AKT pathway.     

Silencing of pkm2 increases the efficacy of docetaxel in human lung cancer xenografts in mice

Tumor aerobic glycolysis, or the Warburg effect, plays important roles in tumor survival, growth, and metastasis. Pyruvate kinase isoenzyme M2 (PKM2) is a key enzyme that regulates aerobic glycolysis in tumor cells. Recent research has shown that PKM2 can be used as a tumor marker for diagnosis and, in particular, as a potential target for cancer therapy. We investigated the effects of combining shRNA targeting PKM2 and docetaxel on human A549 lung carcinoma cells both in vivo and in vitro. We observed that the shRNA can significantly downregulate the expression level of PKM2. The decrease of PKM2 resulted in a decrease in ATP synthesis, which caused intracellular accumulation of docetaxel. Furthermore, the combination of pshRNA‐pkm2 and docetaxel inhibited tumor growth and promoted more cancer cell apoptosis both in vivo and in vitro. Our findings suggest that targeting tumor glycolysis can increase the efficacy of chemotherapy. In particular, the targeting of PKM2 could, to some extent, be a new way of reversing chemotherapy resistance to cancer therapy. (Cancer Sci 2010)