O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth
Jay Prakash SinghKevin QianJeong-Sang LeeJinfeng ZhouXuemei HanBichen ZhangQunxiang OngWeiming NiMingzuo JiangHai‐Bin RuanMin‐Dian LiKaisi ZhangZhaobing DingPhilip LeeKamini SinghJing WuRaimund I. HerzogSusan M. KaechHans-Guido WendelJohn R. YatesWeiping HanRobert S. SherwinYongzhan NieXiaoyong Yang
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PKM2
Anaerobic glycolysis
Acetyltransferases
在房间新陈代谢的改变是许多癌症的一个特征。癌症细胞新陈代谢地被给换新电线支持他们的快速的生长(Kim 和 Dang， 2006；Vander Heiden 等， 2009 ) 。在肿瘤房间观察的描绘最好的新陈代谢的显型是氧气的 glycolysis，也作为 Warburg 效果知道，它甚至在正常的氧集中下面是从高有效的氧化 phosphorylation 的 ATP 产生的移动到低有效 glycolysis (Gatenby 和游猎者的仆从或向导， 2004；Warburg， 1956 ) 。Pyruvate kinase 由从 phosphoenolpyruvate (锐气) 把磷酸盐转移到自动数据处理，从而产生的 pyruvate 和 ATP 在 glycolysis 催化最后的步(Altenberg 和 Greulich， 2004；Corcoran 等， 1976 ) 。在哺乳动物， pyruvate kinase 被二基因， PKLR 和 PKM 编码(Noguchi 等， 1987 ) 。PKM2 是从 PKM 基因的拼接的变体之一，在开发和大多数表示了癌症，和戏在 tumorigenesis 的一个中央角色(Chaneton 和 Gottlieb， 2012；Christofk 等， 2008；……
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Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents.
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Warburg Effect
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Lactic acid production in the presence of high oxygen tensions (aerobic glycolysis) was found to occur in the teleost retina. Forty-two percent more glucose was utilized and 33% more lactic acid was produced under anaerobic than under aerobic conditions. Glycolysis was inhibited 33% by elevated oxygen (Pasteur effect), and it was further demonstrated that glycolysis is dependent upon the integrity of the retinal cells, being almost completely abolished by cellular disruption.
Anaerobic glycolysis
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Aerobic glycolysis is crucial to tumor cells to acquire energy for proliferation and metastasis. Dichlorodiphenyltrichloroethane (DDT), which is a persistent organic pollutant, has been associated with colorectal cancer (CRC) progressions, but the influence of p,p'-DDT on CRC cell metabolism remains unclear. This study showed that exposure to low concentrations of p,p'-DDT from 10-11 to 10-7 M for 48 hours significantly increased glucose uptake and lactate production in colorectal adenocarcinoma cells, which were accompanied by the upregulation of proteins associated with aerobic glycolysis including glucose transporter1, lactate dehydrogenase A, and PDH kinase. We found p,p'-DDT elevated the expression and nucleus translocation of M2 isoform of pyruvate kinase (PKM2), which was responsible for p,p'-DDT-induced enhancement of aerobic glycolysis. Moreover, extracellular signal-regulated kinase (ERK1/2) activation by p,p'-DDT modulated the impacts of p,p'-DDT on PKM2 and aerobic glycolysis. Treatment of p,p'-DDT increased intracellular reactive oxygen species (ROS). N-acetyl-L-cysteine, an ROS inhibitor, prevented p,p'-DDT-induced promotion of aerobic glycolysis, ERK1/2 activation, upregulation, and nucleus translocation of PKM2. Taken together, these results demonstrated that p,p'-DDT promotes aerobic glycolysis via ROS-mediated ERK/PKM2 signaling.
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Anaerobic glycolysis
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The objective of this work was to investigate the influence of phosphoglycerate kinase-1 (PGK1) and pyruvate kinase-M2 (PKM2) activity on glycolysis, myofibrillar proteins, calpain system, and apoptosis pathways of postmortem muscle. The activity of PGK1 and PKM2 was regulated by their inhibitors and activators to construct the postmortem glycolysis vitro model and then incubated at 4 °C for 24 h. The results showed that compared to PGK1 and PKM2 inhibitors groups, the addition of PGK1 and PKM2 activators could accelerate glycogen consumption, ATP and lactate production, while declining pH value. Moreover, the addition of PGK1 and PKM2 activators could increase desmin degradation, μ-calpain activity, and caspase-3 abundance. Interestingly, troponin-T degradation was significantly increased both in PKM2 inhibitor and activator groups. It was suggested that PGK1 and PKM2 might be used as robust indicators to regulate meat quality by affecting the glycolysis, myofibrillar proteins, μ-calpain and apoptosis pathways in postmortem muscle.
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Phosphoglycerate kinase
Myofibril
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Metabolic reprogramming is a hallmark of malignancy. Testes-specific protease 50 (TSP50), a newly identified oncogene, has been shown to play an important role in tumorigenesis. However, its role in tumor cell metabolism remains unclear. To investigate this issue, LC-MS/MS was employed to identify TSP50-binding proteins and pyruvate kinase M2 isoform (PKM2), a known key enzyme of aerobic glycolysis, was identified as a novel binding partner of TSP50. Further studies suggested that TSP50 promoted aerobic glycolysis in HCC cells by maintaining low pyruvate kinase activity of the PKM2. Mechanistically, TSP50 promoted the Warburg effect by increasing PKM2 K433 acetylation level and PKM2 acetylation site (K433R) mutation remarkably abrogated the TSP50-induced aerobic glycolysis, cell proliferation in vitro and tumor formation in vivo. Our findings indicate that TSP50-mediated low PKM2 pyruvate kinase activity is an important determinant for Warburg effect in HCC cells and provide a mechanistic link between TSP50 and tumor metabolism.
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Warburg Effect
Anaerobic glycolysis
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Many cancer cells have increased rates of aerobic glycolysis, a phenomenon termed the Warburg effect. In addition, in tumors there is a predominance of expression of the M2 isoform of pyruvate kinase (PKM2). M2 expression was previously shown to be necessary for aerobic glycolysis and to provide a growth advantage to tumors. We report that knockdown of pyruvate kinase in tumor cells leads to a decrease in the levels of pyruvate kinase activity and an increase in the pyruvate kinase substrate phosphoenolpyruvate. However, lactate production from glucose, although reduced, was not fully inhibited. Furthermore, we are unique in reporting increased serine and glycine biosynthesis from both glucose and glutamine following pyruvate kinase knockdown. Although pyruvate kinase knockdown results in modest impairment of proliferation in vitro, in vivo growth of established xenograft tumors is unaffected by PKM2 absence. Our findings indicate that PKM2 is dispensable for tumor maintenance and growth in vivo, suggesting that other metabolic pathways bypass its function.
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Warburg Effect
Anaerobic glycolysis
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Anaerobic glycolysis
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Pyruvate kinase plays a vital role in regulating cell metabolism. It catalyzes the rate-limiting step of glycolysis, the conversion of Phosphoenolpyruvate (PEP) to Pyruvate with concomitant production of ATP. It consists of four isoforms in mammals, which are tissue-specific PKL, PKR, PKM1, and PKM2. PKL, PKR, and PKM1 exist as stable tetramers, whereas PKM2 subunits form tetramers and dimmers. M2 isoform of Pyruvate Kinase (PKM2) is a crucial regulator and has the unique ability to shift glucose metabolism in favor of cancer cells. In accordance, cancerous state is correlated with high PKM2 expression in a variety of tumor tissues. Besides a crucial metabolic role, a significant chunk of data has unraveled the role of PKM2 in gene transcription and its ability to act as protein kinase. Due to the soaring number of papers dealing with the role of PKM2 in tumorigenesis, it has gained enormous attention in recent past. The review deals with the metabolic role of pyruvate kinase M2 in normal cell versus cancerous cells, and its therapeutic relevance and future directions in the field are also discussed.
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Warburg Effect
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PKM2
Anaerobic glycolysis
Warburg Effect
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