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目的 磷酸甘油酸脱氢酶(phosphoglycerate dehydrogenase,PHGDH)催化糖酵解中间产物3-磷酸甘油酸生成3-磷酸羟基丙酮酸,将糖酵解中间产物引入丝氨酸生物合成途径,它在包括乳腺癌和结肠癌等多种肿瘤中表达升高.本研究旨在探讨PHGDH的表达对胃癌细胞(BGC823)增殖以及对化疗药物顺铂敏感性的影响.方法 免疫组织化学染色检测PHGDH蛋白在75例配对的胃癌和癌旁正常组织中的表达情况;siRNA转染胃癌细胞BGC823干扰PHGDH表达,蛋白质印迹法验证siRNA对PHGDH蛋白表达的干扰效率;CCK-8法和平板克隆实验检测PHGDH基因沉默对胃癌细胞BGC823增殖和克隆形成能力的影响;流式细胞术检测PHGDH基因沉默对BGC823细胞周期的影响;流式细胞术检测凋亡评估PHGDH基因沉默对胃癌细胞BGC823对化疗药物顺铂反应性的影响.结果 PHGDH在胃癌组织中的阳性表达率为72.0%(54/75),显著高于癌旁正常组织的41.3%(31/75),差异有统计学意义,χ2=14.36,P<0.01;在转染siRNA后,实验组BGC823-siPHGDH细胞中的PHGDH/β-actin蛋白表达相对灰度比值为0.09±0.02,显著低于阴性对照组的0.70±0.05和空白对照组的0.74±0.06,差异有统计学意义,F=62.35,P<0.01;CCK-8实验结果显示,细胞铺板后5 d,BGC823-Mock、BGC823-siNC和BGC823-siPHGDH细胞各组在第5天时BGC823细胞增长倍数分别为11.13±0.35、11.30±0.72和5.58±0.66,差异有统计学意义,F=48.61,P<0.01;平板克隆形成实验结果显示,细胞培养14 d后,BGC823-Mock、BGC823-siNC和BGC823-siPHGDH细胞形成的克隆数分别为182.67±11.85、173.33±7.26和28.33±10.93,差异有统计学意义,F=71.85,P<0.01;细胞周期检测结果显示,阴性对照组BGC823-siNC的G0/G1期细胞百分比为(70.3±2.4)%,实验组BGC823-siPHGDH的G0/G1期细胞百分比为(87.5±1.3)%,说明实验组BGC823-siPHGDH的G0/G1期细胞增多,PHGDH基因沉默引起胃癌细胞发生G0/G1细胞周期阻滞;细胞凋亡检测结果显示,经1 μg/mL的顺铂处理BGC823-siNC和BGC823-siPHGDH细胞24 h后,BGC823-siNC凋亡率为(28.8±2.5)%,BGC823-siPHGDH组为(45.0±5.1)%,提示PHGDH基因沉默能够增加胃癌细胞BGC823对顺铂的敏感性.结论 PHGDH基因沉默抑制胃癌细胞BGC823的增殖,引起细胞周期阻滞,增加对化疗药物顺铂的敏感性,这不仅为胃癌临床治疗提供一个新的靶点,而且为肿瘤代谢在肿瘤发生和发展中的作用提供了新的实验证据. 相似文献
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磷脂酰肌醇3激酶(PI3K)-蛋白质丝氨酸苏氨酸激酶(Akt)途径是细胞内重要的信号传导途径,在细胞增殖分化中起重要作用。PI3K-Akt途径的失调控对于多种肿瘤的发生是一种刺激信号,途径中任何激酶表达的异常都可能诱导肿瘤的发生。现综述PI3K-Akt途径中PI3K、Akt、磷脂酰肌醇依赖性蛋白激酶(PDK)、与张力蛋白同源的第10号染色体上丢失的磷酸酶基因 (PTEN)在肿瘤发生发展中的作用。 相似文献
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王耐勤 《国外医学(肿瘤学分册)》1981,(1)
环核苷酸(Cyclic Nucleotides)是机体内某些单核苷酸在环化酶和镁离子作用下产生的一类活性物质,与人体关系密切的环核苷酸有3′,5′环化-磷酸腺苷(cAMP)和3′、5′环化-磷酸乌苷(cGMP)。两者在体内的合成和代谢过程如下: 相似文献
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磷脂酰肌醇3激酶-蛋白质丝氨酸苏氨酸激酶途径与肿瘤的关系 总被引:1,自引:0,他引:1
磷脂酰肌醇3激酶(PI3K)-蛋白质丝氨酸苏氨酸激酶(Akt)途径是细胞内重要的信号传导途径,在细胞增殖分化中起重要作用。PI3K-Akt途径的失调控对于多种肿瘤的发生是一种刺激信号,途径中任何激酶表达的异常都可能诱导肿瘤的发生。现综述PI3K-Akt途径中PI3K、Akt、磷脂酰肌醇依赖性蛋白激酶(PDK)、与张力蛋白同源的第10号染色体上丢失的磷酸酶基因(PTEN)在肿瘤发生发展中的作用。 相似文献
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透明质酸(HA)是细胞外基质(ECM)的主要成分之一。在细胞与ECM及细胞与细胞间的黏附上起重要作用。HA除通过其受体、相关的酶以及多种细胞因子影响细胞迁移、分化、细胞问相互作用外,还可以通过Fas-FasL途径、磷脂酰肌醇3激酶-丝氨酸和转录核因子-κB等因子,影响淋巴细胞、巨噬细胞和树突状细胞的功能,从而广泛参与肿瘤细胞的增殖、分化、浸润和转移。 相似文献
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Zhang Jing Wei Heng Liu Xia Wang Ning Qi Yafei Zhang Yao Zhang Shulan 《Cancer biology & therapy》2015,16(4):541-548
Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of de novo serine biosynthesis. Previous reports have demonstrated that PHGDH plays an important role in some malignancies. However, the biological role of PHGDH in human cervical adenocarcinoma has not been explored. We examined the expression of PHGDH in 54 cervical adenocarcinoma samples by immunohistochemistry and evaluated the association with clinicopathological parameters and prognosis. We performed shRNA transfection to knock down PHGDH gene expression in HeLa cells. A cell proliferation test, cisplatin cytotoxicity test and apoptosis test examined the HeLa cell line after PHGDH knockdown in vitro. In vivo tumorigenesis was assessed using a mouse xenograft model. Moreover, we examined the effects on Bcl-2 and cleaved caspase-3 expression after knockdown of PHGDH and treatment of cisplatin for 48h by Western blot. In this study, we demonstrated that elevated PHGDH expression was found in cervical adenocarcinoma and was associated with tumor size and prognosis. Knocking down PHGDH in HeLa cells significantly inhibited cell proliferation and increased cisplatin chemotherapy sensitivity. Silencing PHGDH resulted in inhibition of tumorigenesis in vivo. Furthermore, PHGDH knockdown reduced Bcl-2 and increased cleaved caspase-3 expression. Collectively, our study indicates the novel roles of PHGDH in cervical adenocarcinoma and identifies PHGDH as a new anticancer target. 相似文献
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Alexey Antonov Massimiliano Agostini Maria Morello Marilena Minieri Gerry Melino Ivano Amelio 《Oncotarget》2014,5(22):11004-11013
Serine and glycine are amino acids that provide the essential precursors for the synthesis of proteins, nucleic acids and lipids. Employing 3 subsequent enzymes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine phosphatase (PSPH), phosphoserine aminotransferase 1 (PSAT1), 3-phosphoglycerate from glycolysis can be converted in serine, which in turn can by converted in glycine by serine methyl transferase (SHMT). Besides proving precursors for macromolecules, serine/glycine biosynthesis is also required for the maintenance of cellular redox state. Therefore, this metabolic pathway has a pivotal role in proliferating cells, including cancer cells. In the last few years an emerging literature provides genetic and functional evidences that hyperactivation of serine/glycine biosynthetic pathway drives tumorigenesis. Here, we extend these observations performing a bioinformatics analysis using public cancer datasets. Our analysis highlighted the relevance of PHGDH and SHMT2 expression as prognostic factor for breast cancer, revealing a substantial ability of these enzymes to predict patient survival outcome. However analyzing patient datasets of lung cancer our analysis reveled that some other enzymes of the pathways, rather than PHGDH, might be associated to prognosis. Although these observations require further investigations they might suggest a selective requirement of some enzymes in specific cancer types, recommending more cautions in the development of novel translational opportunities and biomarker identification of human cancers. 相似文献
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Jinyun Chen Franklin Chung Guizhi Yang Minying Pu Hui Gao Wei Jiang Hong Yin Vladimir Capka Shailaja Kasibhatla Bryan Laffitte Savina Jaeger Raymond Pagliarini Yaoyu Chen Wenlai Zhou 《Oncotarget》2013,4(12):2502-2511
Cancer cells rely on aerobic glycolysis to maintain cell growth and proliferation via the Warburg effect. Phosphoglycerate dehydrogenase (PHDGH) catalyzes the first step of the serine biosynthetic pathway downstream of glycolysis, which is a metabolic gatekeeper both for macromolecular biosynthesis and serine-dependent DNA synthesis. Here, we report that PHDGH is overexpressed in many ER-negative human breast cancer cell lines. PHGDH knockdown in these cells leads to a reduction of serine synthesis and impairment of cancer cell proliferation. However, PHGDH knockdown does not affect tumor maintenance and growth in established breast cancer xenograft models, suggesting that PHGDH-dependent cancer cell growth may be context-dependent. Our findings suggest that other mechanisms or pathways may bypass exclusive dependence on PHGDH in established human breast cancer xenografts, indicating that PHGDH is dispensable for the growth and maintenance of tumors in vivo. 相似文献
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Luo W Yan G Li L Wang Z Liu H Zhou S Liu S Tang M Yi W Dong Z Cao Y 《Molecular carcinogenesis》2008,47(12):934-946
We have previously elucidated that Epstein-Barr-virus-encoded latent membrane protein 1 (LMP1) can increase the serine phosphorylation level of annexin A2 by activating the protein kinase C (PKC) signaling pathway and that LMP1 induces the nuclear entry of annexin A2 in an energy- and temperature-dependent manner. Here, we further confirm that LMP1 increases the serine phosphorylation level of annexin A2 by activating the phosphoinositide-specific phospholipase C (PI-PLC)-PKC alpha/PKC beta pathway, mainly through the activation of the PKCbeta pathway. Additionally, active recombinant PKC alpha, PKC beta I, and PKC beta II kinases are able to phosphorylate annexin A2 in vitro. Annexin A2 in the nucleus plays an important role in DNA synthesis and cell proliferation. By site-specific substitution of glutamic acid in the place of serine 11 and 25 in the N-terminus, we show that serine 25 phosphorylation of annexin A2 was associated with the nuclear entry of annexin A2, DNA synthesis and cell proliferation, whereas serine 11 has no obvious influence. We demonstrate for the first time that the PI-PLC-PKCalpha/PKCbeta pathway plays an important role in serine phosphorylation and in the nuclear entry of annexin A2 mediated by LMP1. In addition, we show that annexin A2 is the substrate protein of PKC alpha, PKC betaI, and PKC betaII kinases. Serine 25 phosphorylation of annexin A2 is shown to be associated with its nuclear entry, DNA synthesis, and cell proliferation. 相似文献
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Metabolism of bladder cancer represents a key issue for cancer research. Several metabolic altered pathways are involved in bladder tumorigenesis, representing therefore interesting targets for therapy.Tumor cells, including urothelial cancer cells, rely on a peculiar shift to aerobic glycolysis-dependent metabolism (the Warburg-effect) as the main energy source to sustain their uncontrolled growth and proliferation. Therefore, the high glycolytic flux depends on the overexpression of glycolysis-related genes (SRC-3, glucose transporter type 1 [GLUT1], GLUT3, lactic dehydrogenase A [LDHA], LDHB, hexokinase 1 [HK1], HK2, pyruvate kinase type M [PKM], and hypoxia-inducible factor 1-alpha [HIF-1α]), resulting in an overproduction of pyruvate, alanine and lactate. Concurrently, bladder cancer metabolism displays an increased expression of genes favoring the pentose phosphate pathway (glucose-6-phosphate dehydrogenase [G6PD]) and the fatty-acid synthesis (fatty acid synthase [FASN]), along with a decrease of AMP-activated protein kinase (AMPK) and Krebs cycle activities. Moreover, the PTEN/PI3K/AKT/mTOR pathway, hyper-activated in bladder cancer, acts as central regulator of aerobic glycolysis, hence contributing to cancer metabolic switch and tumor cell proliferation.Besides glycolysis, glycogen metabolism pathway plays a robust role in bladder cancer development. In particular, the overexpression of GLUT-1, the loss of the tumor suppressor glycogen debranching enzyme amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL), and the increased activity of the tumor promoter enzyme glycogen phosphorylase impair glycogen metabolism. An increase in glucose uptake, decrease in normal cellular glycogen storage, and overproduction of lactate are consequences of decreased oxidative phosphorylation and inability to reuse glucose into the pentose phosphate and de novo fatty acid synthesis pathways. Moreover, AGL loss determines augmented levels of the serine-to-glycine enzyme serine hydroxymethyltransferase-2 (SHMT2), resulting in an increased glycine and purine ring of nucleotides synthesis, thus supporting cells proliferation.A deep understanding of the metabolic phenotype of bladder cancer will provide novel opportunities for targeted therapeutic strategies. 相似文献
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To evaluate the expression levels of serine/glycine metabolism-related proteins (PHGDH, PSAT, PSPH, SHMT, and GLDC) in six different subtypes of triple negative breast cancer (TNBC) patients and gain insight into their implications. Formalin-fixed, paraffin-embedded tissues from 129 TNBC patients were assembled into tissue microarrays. Immunohistochemical staining was performed for serine/glycine metabolism-related proteins (PHGDH, PSAT, PSPH, SHMT, and GLDC) and surrogate immunohistochemical markers (CK5/6, EGFR, claudin 3, claudin 4, claudin 7, E-cadherin, STAT1, interleukin-8 [IL-8], AR, and GGT-1) for identifying the molecular subtype of TNBC. TNBC subtype classifications included the following: basal-like (CK5/6-positive and/or EGFR-positive), molecular apocrine (AR-positive and/or GGT-1-positive), claudin-low (claudin 3-, claudin 4-, claudin 7-negative and/or E-cadherin-negative), immune-related (IL-8-negative and stromal STAT1-positive), mixed (features from two or more of the four subtypes), and null (no features from any of the four subtypes). Tissues from basal marker-positive patients showed increased expression levels of tumoral PHGDH compared with those from basal marker-negative patients (p?=?0.029); lack of stromal SHMT1 expression was significantly correlated with T stage (p?=?0.016). Multivariate Cox analysis revealed that a lack of stromal SHMT1 expression was an independent prognostic factor for predicting a shorter disease-free survival period (hazard ratio 4.002, 95 % confidence interval [CI] 1.077–14.83, p?=?0.038); furthermore, a lack of tumoral PHGDH expression was predictive of a shorter overall survival rate (hazard ratio 3.053, 95 % CI 1.002–9.305, p?=?0.050). In conclusion, the most abundantly expressed serine/glycine metabolism-related protein in basal-like TNBC tissues was tumoral PHGDH, and expression levels of stromal SHMT1 and tumoral PHGDH were inversely correlated with clinical prognostic factors. Also, this study is the first to assess serine/glycine relationships at the protein level in regards to clinical outcomes. 相似文献
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Luo J 《Breast cancer research : BCR》2011,13(6):317-3
Exemplified by the cancer cell's preference for glycolysis (the Warburg effect), altered metabolism has taken centerstage
as an emerging hallmark of cancer. Charting the landscape of cancer metabolic addictions should reveal new avenues for therapeutic
attack. Two recent studies found subsets of human melanoma and breast cancers to have high levels of phosphoglycerate dehydrogenase
(PHGDH), a key enzyme for serine biosynthesis, and these cancer cells are dependent on PHGDH for their growth and survival.
Tumors may thus harbor distinct metabolic alterations to support their malignancy, and targeting enzymes such as PHGDH might
prove a viable therapeutic strategy in this scenario. 相似文献