肿瘤转移过程中的细胞代谢调控

转移是90%癌症患者死亡的主要原因。相比原位肿瘤,转移的肿瘤表现出截然不同的代谢特征。这些代谢上的异常在肿瘤细胞迁移、侵袭、抗失巢凋亡及远端定植过程中发挥重要作用。因此,深入理解肿瘤转移过程中的代谢重编程机制,有助于利用肿瘤细胞的代谢弱点限制肿瘤转移,进而为发生转移的癌症患者提供有效治疗手段。     

肿瘤糖代谢及靶向治疗策略研究进展

代谢异常是肿瘤的重要特征之一。肿瘤细胞通过代谢重编程来满足恶性增殖所需的能量和生物大分子,并维持氧化还原稳态,促进癌细胞的存活和转移。肿瘤细胞内的代谢酶重塑和肿瘤微环境共同驱动肿瘤细胞代谢重编程,进而促进肿瘤的发生发展。该文综述了肿瘤糖代谢重编程的过程和作用,并结合该实验室的研究工作提出靶向肿瘤代谢的治疗策略。     

肿瘤干细胞生物学特性及其干性维持机制的研究进展

肿瘤是威胁人类健康和社会发展最为严重的疾病之一,也是全球第二大常见疾病死因。最新统计数据显示,恶性肿瘤在发达国家已取代心血管疾病成为第一大疾病死因。肿瘤的耐药、转移和复发,仍然是临床治疗中亟需解决的难题。肿瘤干细胞(tumor stem cells, TSCs)是一类具有自我更新、分化潜能、高致瘤性和高耐药性等特征的细胞亚群,能够抵抗放化疗等非特异性治疗手段,在肿瘤发生、转移、耐药和复发中发挥关键作用。肿瘤干细胞标志物、干性维持机制、微环境和代谢重编程等领域已成为了研究热点,最新研究成果为肿瘤干细胞的鉴定和靶向治疗提供了新的靶标和策略。本文对肿瘤干细胞的表面标志物(CD133和CD44等)、自我更新和上皮细胞间充质转化(epithelial mesenchymal transition, EMT)信号通路(Wnt/β-catenin和Hedgehog等)、微环境特征、代谢重编程(糖酵解和氧化磷酸化等),及其在肿瘤的起始、发展、转移和耐药中的作用进行了综述。     

尿素循环关键酶在肿瘤中的作用和机制

尿素循环是将机体代谢产生的氨经过一系列酶促反应生成尿素的过程,对于维持体内氨基酸水平及氨稳态有着重要的作用.完整的尿素循环几乎只在肝脏中进行,因此癌症中的尿素循环通常处于失调状态,肿瘤细胞可以通过调节尿素循环酶的表达来适应环境和调控生物合成,同时尿素循环失调会暴露出癌症的短板,了解尿素循环在癌症中的演变可以用于癌症的诊断和治疗.本文主要介绍尿素循环酶在不同肿瘤中的差异性调控,了解尿素循环在肿瘤细胞中的重编程,总结了尿素循环和肿瘤微环境、肿瘤治疗之间的关系.     

代谢组学在肿瘤药物靶点筛选中的应用进展

肿瘤是一种多因素参与造成机体各系统功能平衡紊乱的代谢性疾病,代谢重编程是恶性肿瘤的重要特征之一.研究"代谢指纹图谱"的代谢组学,通过揭示肿瘤或药物引起的宿主内源性代谢物的变化,为肿瘤药物靶点的筛选提供了可能.但目前对代谢组在肿瘤药物靶点筛选中的整体性综述并不多见,因此,本文在介绍了代谢组学筛选肿瘤药物靶点的流程的基础上...     

紫苏种子脂肪酸组成及合成代谢研究进展

紫苏是一种新型油料作物,种子含油量为35%左右,紫苏籽油脂肪酸组成丰富,含有棕榈酸(16:0)、硬脂酸(18:0)、油酸(18:1)、亚油酸(18:2)和α-亚麻酸(18:3)等,其中α-亚麻酸(ALA)含量高达60%,广泛用于功能性保健食品、药物及油脂化工业.介绍紫苏种子脂肪酸组成及合成代谢基本途径,对近年来脂肪酸合成代谢基因工程研究进行概述与展望.     

GGPPS及其抑制剂在肿瘤中的研究进展

香叶基香叶基焦磷酸合酶(geranylgeranyl diphosphate synthase,GGPPS)是甲羟戊酸途径中的一种分支酶,参与蛋白质异戊二烯化。GGPPS通过介导多条细胞信号通路,在细胞的生物学功能和疾病的发生机制中发挥关键作用,调节各种疾病的病理进展。GGPPS在肿瘤中表达异常,而表达水平与预后密切相关,故有望成为肿瘤早期诊治的一种新兴的生物指标。本文主要对GGPPS的生物学功能、在肿瘤中的作用及其抑制剂在肿瘤中的应用进行总结,寻求其在未来肿瘤疾病防治中的潜在价值。     

肿瘤有氧糖酵解的研究进展CSCD

代谢重编程是肿瘤细胞重要的标志特征。本文通过介绍恶性肿瘤细胞己糖激酶(HK)、丙酮酸激酶(PK)、磷酸果糖激酶(PFK)、葡萄糖转运蛋白(GLUT)等糖酵解过程中关键酶;PI3K/PKB、m TOR和AMPK等细胞信号转导途径;p53、c-myc和HIF-1等转录因子在肿瘤细胞有氧糖酵解中的研究进展,进而深入了解其在肿瘤诊断和治疗中具有的潜在价值。     

TRIM29在肿瘤中的研究进展

TRIM29蛋白属于TRIM蛋白家族,是一种E3泛素连接酶,它在肿瘤的增殖、侵袭转移、耐药及肿瘤免疫中都具有十分重要的作用,且其功能具有细胞和组织特异性.TRIM29蛋白可通过与p53的相互作用促进肿瘤细胞的增殖;通过促进肿瘤细胞上皮-间质转化、激活经典的Wnt信号通路等增强肿瘤细胞的侵袭转移能力.高表达的TRIM29...     

脂代谢重编程在肝癌恶性演进中的最新研究进展

肝癌是一种非常常见的消化道肿瘤,其恶性程度高,发病隐匿,早期可无症状,且发病率也在逐年升高。代谢重编程是癌细胞为了满足细胞快速生长所需的大量能量,使其代谢方式发生改变。尽管与其他代谢变化(例如葡萄糖和谷氨酰胺代谢)相比,癌细胞中脂肪酸代谢的变化受到的关注较少,但最近的研究逐渐发现了脂类代谢重编程在癌变过程中的重要性。该文以脂代谢重编程为基础,介绍其在肝癌恶性演进中的最新进展。     

Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer

Leflunomide (Lef) is an agent used in autoimmune disorders that interferes with DNA synthesis. De Novo pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combination with Gem, in a syngeneic mouse model of pancreatic cancer.Methods: MTS proliferation assays were conducted to assess growth inhibition by Gem (0-20 nM), Lef (0-40 uM) and Gem+Lef in KPC (KrasLSL.G12D/+;p53R172H/+; PdxCretg/+) cells in vitro. An in vivo heterotopic KPC model was used and cohorts were treated with: PBS (control), Gem (75 mg/kg/q3d), Lef (40 mg/kg/d), or Gem+Lef. At d28 post-treatment, tumor burden, proliferation index (Ki67), and vascularity (CD31) were measured. Changes in the frequency of peripheral and intratumoral immune cell subsets were evaluated via FACS. Liquid chromatography-mass spectrometry was used for metabolomics profiling.Results: Lef inhibits KPC cell growth and synergizes with Gem in vitro (P<0.05; Combination Index 0.44 (<1 indicates synergy). In vivo, Lef alone and in combination with Gem delays KPC tumor progression (P<0.001). CTLA-4+T cells are also significantly decreased in tumors treated with Lef, Gem or in combination (Gem+Lef) compared to controls (P<0.05). Combination therapy also decreased the Ki67 and vascularity (P<0.01). Leflunomide inhibits de novo pyrimidine synthesis both in vitro (p<0.0001) and in vivo (p<0.05).Conclusions: In this study, we demonstrated that Gem+Lef inhibits pancreatic cancer growth, decrease T cell exhaustion, vascularity and as proof of principle inhibits de novo pyrimidine synthesis. Further characterization of changes in adaptive immunity are necessary to characterize the mechanism of tumor growth inhibition and facilitate translation to a clinical trial.     

Whole‐cell biocatalytic and de novo production of alkanes from free fatty acids in Saccharomyces cerevisiae

Rapid global industrialization in the past decades has led to extensive utilization of fossil fuels, which resulted in pressing environmental problems due to excessive carbon emission. This prompted increasing interest in developing advanced biofuels with higher energy density to substitute fossil fuels and bio‐alkane has gained attention as an ideal drop‐in fuel candidate. Production of alkanes in bacteria has been widely studied but studies on the utilization of the robust yeast host, Saccharomyces cerevisiae, for alkane biosynthesis have been lacking. In this proof‐of‐principle study, we present the unprecedented engineering of S. cerevisiae for conversion of free fatty acids to alkanes. A fatty acid α‐dioxygenase from Oryza sativa (rice) was expressed in S. cerevisiae to transform C_12–18 free fatty acids to C_11–17 aldehydes. Co‐expression of a cyanobacterial aldehyde deformylating oxygenase converted the aldehydes to the desired alkanes. We demonstrated the versatility of the pathway by performing whole‐cell biocatalytic conversion of exogenous free fatty acid feedstocks into alkanes as well as introducing the pathway into a free fatty acid overproducer for de novo production of alkanes from simple sugar. The results from this work are anticipated to advance the development of yeast hosts for alkane production. Biotechnol. Bioeng. 2017;114: 232–237. © 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.     

Role of fatty acid elongases in determination of de novo synthesized monounsaturated fatty acid species

Enhanced production of monounsaturated fatty acids (FA) derived from carbohydrate-enriched diets has been implicated in the development of obesity and insulin resistance. The FA elongases Elovl-5 and Elovl-6 are regulated by nutrient and hormone status, and have been shown using intact yeast and mammalian microsome fractions to be involved in the synthesis of monounsaturated FAs (MUFA). Herein, targeted knockdown and overexpression of Elovl-5 or Elovl-6 was used to determine their roles in de novo synthesis of specific MUFA species in mammalian cells. Treatment of rat insulinoma (INS)-1 cells with elevated glucose increased de novo FA synthesis and the ratio of MUFAs to saturated FAs. Elovl-5 knockdown decreased elongation of 16:1,n-7. Elovl-5 overexpression increased synthesis of 18:1,n-7; however, this increase was dependent on stearoyl-CoA desaturase–driven 16:1,n-7 availability. Knockdown of Elovl-6 decreased elongation of 16:0 and 16:1,n-7, resulting in accumulation of 16:1,n-7. Elovl-6 overexpression preferentially drove synthesis of 16:0 elongation products 18:0 and 18:1,n-9 but not 18:1,n-7. These findings demonstrate that coordinated induction of FA elongase and desaturase activity is required for balanced synthesis of specific n-7 versus n-9 MUFA species. Given the relative abundance of 16:0 to 16:1,n-7 and the specificity of Elovl-6 for 16:0, Elovl-6 is a major elongase for 18:1,n-9 production.     

De novo fatty acid synthesis at the mitotic exit is required to complete cellular division

Although the regulation of the cell cycle has been extensively studied, much less is known about its coordination with the cellular metabolism. Using mass spectrometry we found that lysophospholipid levels decreased drastically from G₂/M to G₁ phase, while de novo phosphatidylcholine synthesis, the main phospholipid in mammalian cells, increased, suggesting that enhanced membrane production was concomitant to a decrease in its turnover. In addition, fatty acid synthesis and incorporation into membranes was increased upon cell division. The rate-limiting reaction for de novo fatty acid synthesis is catalyzed by acetyl-CoA carboxylase. As expected, its inhibiting phosphorylation decreased prior to cytokinesis initiation. Importantly, the inhibition of fatty acid synthesis arrested the cells at G₂/M despite the presence of abundant fatty acids in the media. Our results suggest that de novo lipogenesis is essential for cell cycle completion. This “lipogenic checkpoint” at G₂/M may be therapeutically exploited for hyperproliferative diseases such as cancer.     

The metabolic switch and its regulation in cancer cells

The primary features of cancer are maintained via intrinsically modified metabolic activity, which is characterized by enhanced nutrient supply, energy production, and biosynthetic activity to synthesize a variety of macromolecular components during each passage through the cell cycle. This metabolic shift in transformed cells, as compared with non-proliferating cells, involves aberrant activation of aerobic glycolysis, de novo lipid biosynthesis and glutamine-dependent anaplerosis to fuel robust cell growth and proliferation. Here, we discuss the unique metabolic characteristics of cancer, the constitutive regulation of metabolism through a variety of signal transduction pathways and/or enzymes involved in metabolic reprogramming in cancer cells, and their implications in cancer diagnosis and therapy.     

Quantitative chemical proteomics profiling of de novo protein synthesis during starvation-mediated autophagy

Autophagy is an intracellular degradation mechanism in response to nutrient starvation. Via autophagy, some nonessential cellular constituents are degraded in a lysosome-dependent manner to generate biomolecules that can be utilized for maintaining the metabolic homeostasis. Although it is known that under starvation the global protein synthesis is significantly reduced mainly due to suppression of MTOR (mechanistic target of rapamycin serine/threonine kinase), emerging evidence demonstrates that de novo protein synthesis is involved in the autophagic process. However, characterizing these de novo proteins has been an issue with current techniques. Here, we developed a novel method to identify newly synthesized proteins during starvation-mediated autophagy by combining bio-orthogonal noncanonical amino acid tagging (BONCAT) and isobaric tags for relative and absolute quantitation (iTRAQ^TM). Using bio-orthogonal metabolic tagging, L-azidohomoalanine (AHA) was incorporated into newly synthesized proteins which were then enriched with avidin beads after a click reaction between alkyne-bearing biotin and AHA's bio-orthogonal azide moiety. The enriched proteins were subjected to iTRAQ labeling for protein identification and quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Via the above approach, we identified and quantified a total of 1176 proteins and among them 711 proteins were found to meet our defined criteria as de novo synthesized proteins during starvation-mediated autophagy. The characterized functional profiles of the 711 newly synthesized proteins by bioinformatics analysis suggest their roles in ensuring the prosurvival outcome of autophagy. Finally, we performed validation assays for some selected proteins and found that knockdown of some genes has a significant impact on starvation-induced autophagy. Thus, we think that the BONCAT-iTRAQ approach is effective in the identification of newly synthesized proteins and provides useful insights to the molecular mechanisms and biological functions of autophagy.     

Lipid metabolism reprogramming in colorectal cancer

The hallmark feature of metabolic reprogramming is now considered to be widespread in many malignancies, including colorectal cancer (CRC). Of the gastrointestinal tumors, CRC is one of the most common with a high metastasis rate and long insidious period. The incidence and mortality of CRC has increased in recent years. Metabolic reprogramming also has a significant role in the development and progression of CRC, especially lipid metabolic reprogramming. Many studies have reported that lipid metabolism reprogramming is similar to the Warburg effect with typical features affecting tumor biology including proliferation, migration, local invasion, apoptosis, and other biological behaviors of cancer cells. Therefore, studying the role of lipid metabolism in the occurrence and development of CRC will increase our understanding of its pathogenesis, invasion, metastasis, and other processes and provide new directions for the treatment of CRC. In this paper, we mainly describe the molecular mechanism of lipid metabolism reprogramming and its important role in the occurrence and development of CRC. In addition, to provide reference for subsequent research and clinical diagnosis and treatment we also review the treatments of CRC that target lipid metabolism.     

Localized de novo phospholipid synthesis drives autophagosome biogenesis

ABSTRACT

During (macro)autophagy, cells form transient organelles, termed autophagosomes, to target a broad spectrum of substrates for degradation critical to cellular and organismal health. Driven by rapid membrane assembly, an initially small vesicle (phagophore) elongates into a large cup-shaped structure to engulf substrates within a few minutes in a double-membrane autophagosome. In particular, how autophagic membranes expand has been a longstanding question. Here, we summarize our recent work that delineates a pathway that drives phagophore expansion by localized de novo phospholipid synthesis. Specifically, we found that the conserved acyl-CoA synthetase Faa1 localizes to nucleated phagophores to locally activate fatty acids for de novo phospholipid synthesis in the neighboring ER. These newly synthesized phospholipids are then preferentially incorporated into autophagic membranes and drive the expansion of the phagophore into a functional autophagosome. In summary, our work uncovers molecular principles of how cells coordinate phospholipid synthesis and flux with autophagic membrane formation during autophagy.

Abbreviations: ACS: acyl-CoA synthestases; CoA: coenzyme A; ER: endoplasmic reticulum     

Effects of hydrocortisone on carbohydrase concentrations, de novo synthesis and turnover patterns in immature rat intestine

Hydrocortisone administration to infant rats enhanced cellobiase and maltase activities and induced precocious expression of sucrase and trehalase activities along the length of the small intestine. These activity changes reflected proportional concentration increases in the enzymes lactase (EC 3.2.1.23), maltase/glucoamylase (EC 3.2.1.20) and sucrase-isomaltase (EC 3.2.1.48/10). Administration of an equivalent tracer dose of [3H]leucine (by body weight) to control and hydrocortisone-treated infant rats resulted in greater accumulation of label in the carbohydrase pools of the treated rats, suggesting their increased de novo synthesis. The increased concentrations of lactase and maltase/glucoamylase induced by exogenous hydrocortisone were matched by the presence of corresponding greater amounts of label in their brush border pools. Accumulation of label in each of the lactase, maltase/glucoamylase and sucrase-isomaltase pools was generally similar in the hydrocortisone-treated rats, suggesting equivalent stimulation of their synthesis as a group by the humoral agent. The turnover rates of the carbohydrases as a group were found to be similar and did not appear to differ in control and hydrocortisone-treated rats. Total protein synthesis rates were slightly greater in the intestine of the hydrocortisone-treated group of rats.     

Potato cold hardiness development and abscisic acid. II. De novo synthesis of proteins is required for the increase in free abscisic acid during potato (Solanum commersonii) cold acclimation

During cold acclimation of potato plantlets ( Solanum commersonii Dun, PI 458317), there are two transitory increases in free ABA content corresponding to a three-fold increase on the 2nd day and a five-fold increase on the 6th day (Ryu and Li 1993). During this period, plantlets increased in cold hardiness from −5°C (killing temperature, control grown at 22/18°C, day/night) to −10°C by the 7th day of exposure to 4/2°C (day/night). This increase in free ABA was not found when cycloheximide (CHI), an inhibitor of cytoplasmic protein synthesis, was added to the culture medium 6 h before exposure to low temperatures. Plantlets treated with CHI did not acclimate to cold, maintaining a hardiness level (−5°C) similar to that of the 22/18°C-grown plantlets. When the CHI-treated plantlets were exposed to low temperatures for 3 days, transferred to CHI-free culture medium and grown at low temperatures, the plantlets showed a transitory increase in free ABA 2 days later. This increase was followed by the development of cold hardiness (−8°C). Application of CHI to the culture medium after 3 days of cold acclimation, when the first ABA peak and a partial development of cold hardiness (−8°C) had occurred, blocked the second transitory increase in free ABA and resulted in no further development of cold hardiness. These results suggest that de novo synthesis of proteins is required for these transitory increases in free ABA during cold acclimation of potato plantlets.