1、Tumor and aerobic glycolysis,Department of physiology and neurobiology Zhengzhou University Zhao Wenchao,Tumor,Robert A. Weinberg, et al. The Hallmarks of Cancer. Cell, 2000.,1. Self-sufficiency in growth signals,2. Insensitivity to antigrowth signals,3. Evading apoptosis,4. Limitless replicative po
2、tential,5. Sustained angiogenesis,6. Tissue invasion and metastasis,7. Aerobic glycolysis,Glucose,hexokinase,glucose-6-phosphate,fructose-6-phosphate,phosphoglucose isomerase,fructose l, 6 bisphosphate,glyceraldehyde-3-phosphate,dihydroxyacetone phosphate,aldolase,glyceraldehyde-3-phosphate dehydrog
3、enase,1, 3-biphosphoglycerate,phosphoglycerate kinase,3-phosphoglycerate,6-phosphofructokinase1,2-phosphoglycerate,phosphoglycerate mutase,phosphoenolpyruvate,enolase,pyruvate,pyruvate kinase,TCA,lactate,lactate dehydrogenase,Otto Heinrich Warburg,Lactate production increase,Glucose consumption incr
4、ease,Warburg effect,Aerobic glycolysis,Increased glycolysis,1. Response to hypoxia,1920s,(1) In the early stage of tumor development, tumor cells are restricted in stroma without blood vessels due to intact basement menbrane,(2) Diffusion of O2 for over 150m is impossible,(3) No tumor cells can live
5、 160m away from blood vessels,Otto Heinrich Warburg,Lactate production increase,Glucose consumption increase,Warburg effect,Aerobic glycolysis,Increased glycolysis,1. Response to hypoxia,2. Provide matetials for proliferation,Glucose,glucose-6-phosphate,fructose l, 6 bisphosphate,glyceraldehyde-3-ph
6、osphate,dihydroxyacetone phosphate,3-phosphoglycerate,pentose phosphate pathway,ribose-5-phosphate,fatty acid,serine,Otto Heinrich Warburg,Lactate production increase,Glucose consumption increase,Warburg effect,Aerobic glycolysis,Increased glycolysis,1. Response to hypoxia,2. Provide materials for p
7、roliferation,3. Provide acid microenvioment,3. Provide acid microenvioment,Activates matrix metalloproteinase (MMP),Otto Heinrich Warburg,Lactate production increase,Glucose consumption increase,Warburg effect,Aerobic glycolysis,Increased glycolysis,1. Response to hypoxia,2. Provide matetials for pr
8、oliferation,3. Provide acid microenvioment,4. Provide energy rapidly,Glucose,hexokinase,glucose-6-phosphate,fructose-6-phosphate,phosphoglucose isomerase,fructose l, 6 bisphosphate,glyceraldehyde-3-phosphate,dihydroxyacetone phosphate,aldolase,glyceraldehyde-3-phosphate dehydrogenase,1, 3-biphosphog
9、lycerate,phosphoglycerate kinase,3-phosphoglycerate,6-phosphofructokinase1,2-phosphoglycerate,phosphoglycerate mutase,phosphoenolpyruvate,enolase,pyruvate,pyruvate kinase,lactate,lactate dehydrogenase,Hexokinase, HK,1. Unidirection,Glucose,glucose-6-phosphate (G6P),2. Activity of HK is inhibited by
10、G6P,3. Dependent of ATP, activity of HK is inhibited by ADP,4. Two forms: free and binding to mitochondrion,HK,HK,HK ,HK ,Most tissues,Low expression in fat, muscle, heart,Low expression in liver, kidney, intestine,liver, pancreas,Distribution,Km,0.02 mM,0.02 mM,0.02 mM,5 mM,tumor,HK,1. Overexpressi
11、on in cancer of breast, lung, gastrointestine, liver, pancreas, etc,2. Overexpression is positively related to poor prognosis, growth, migration, invasion,3. Higher expression in undifferentiated colon cancer than in differentiated ones,4. In the solid tumor, higher expression in central part than i
12、n border,5. Increase in binding to mitochondrion in maligant tumor,Glucose,hexokinase,glucose-6-phosphate,fructose-6-phosphate,phosphoglucose isomerase,fructose l, 6 bisphosphate,glyceraldehyde-3-phosphate,dihydroxyacetone phosphate,aldolase,glyceraldehyde-3-phosphate dehydrogenase,1, 3-biphosphogly
13、cerate,phosphoglycerate kinase,3-phosphoglycerate,6-phosphofructokinase1,2-phosphoglycerate,phosphoglycerate mutase,phosphoenolpyruvate,enolase,pyruvate,pyruvate kinase,lactate,lactate dehydrogenase,6-phosphofructokinase1, PFK1,fructose-6-phosphate,fructose l, 6 bisphosphate,1. Unidirection,2. PFK1
14、activity is inhibited by ATP, citrate, long-chain fatty acids, lactate and stimulated by ADP/AMP.,3. PFK1 activity is stimulated by fructose 2, 6 bisphosphate .,PFK2,fructose 2, 6 bisphosphate,+,Feed-forward,PFK1,M type,L type,P type,Muscle,Liver, kindey,Platelet,High expression in tumor,Less sensit
15、ive to ATP and citrate,More sensitive to 2,6FBP,PFK2,Poor prognosis and metastasis,Glucose,hexokinase,glucose-6-phosphate,fructose-6-phosphate,phosphoglucose isomerase,fructose l, 6 bisphosphate,glyceraldehyde-3-phosphate,dihydroxyacetone phosphate,aldolase,glyceraldehyde-3-phosphate dehydrogenase,1
16、, 3-biphosphoglycerate,phosphoglycerate kinase,3-phosphoglycerate,6-phosphofructokinase1,2-phosphoglycerate,phosphoglycerate mutase,phosphoenolpyruvate,enolase,pyruvate,pyruvate kinase,lactate,lactate dehydrogenase,Pyruvate kinase, PK,PKL,PKR,PKM1,PKM2,liver and kidneys,erythrocyte,muscle, heart , b
17、rain,self-renewing cells: stem cells, tumor cells,embryogenesis,PKM2,differentiation,PKM1/L/R,tumor,PKM2,dimer,PKM2,tetramer,Km,0.03 mM,0.46 mM,activity,high,low,tissue,normal cells,tumor,Glucose,glucose-6-phosphate,fructose l, 6 bisphosphate,glyceraldehyde-3-phosphate,dihydroxyacetone phosphate,3-p
18、hosphoglycerate,phosphoenolpyruvate,pyruvate,PKM2,breast cancer, bladder carcinoma, colon cancer, esophageal squamous cell cancer, glioma, head and neck cancer, liver cancer, lung carcinoma, meningiomas, renal cell carcinoma,overexpression in tumors:,increases in serum,patients with colon, breast, u
19、rological, lung, cervix, and gastrointestinal tumor,detected in the feces,patients with gastric and colorectal cancer,fructose l, 6 bisphosphate,dimer,tetramer,Tyrosine kinase,Inhibition the binding of 2,6FBP to PKM2,3-phosphoglycerate,Glucose,phosphoenolpyruvate,serine,+,Glucose transporter,sodium-
20、dependent glucose transporter, SGLT,facilitative glucose transporter, GLUT,active,passive,SGLT,SGLT,SGLT1,SGLT2,SGLT3,SGLT4,SGLT5,SGLT6,small intestine, trachea, kidney, heart, colon,kidney,small intestine,small intestine, kidney,kidney,spinal cord, kidney, brain, small intestine,SGLT1,colorectal, h
21、ead and neck, and prostate tumors,metastatic lesions of lung, pancreatic adenocarcinomas, and head and neck cancers,SGLT2,colorectal, gastrointestinal, head and neck, kidney tumors,metastatic lesions of lung, pancreatic adenocarcinomas, and head and neck cancers,GLUT,GLUT1-14,GLUT1,different express
22、ion in different cancers,high affinity for glucose and insensitive to insulin,erythrocytes, placenta, endothelial cells,GLUT2,lowest affinity for glucose, also transport fructose,liver, pancreatic islet cells, retina, stomach,overexpression in gastric tumors,was not detected in insulinomas or other
23、types of islet cell tumors,GLUT3,overexpression in many tunors,brain, placenta, testes,means poor prognosis,highest affinity for glucose and insensitive to insulin,GLUT4,cardiac muscle, skeletal muscle, adipose,overexpression in gastric and breast cancer,GLUT5,kidneys, testes, small intestine, muscl
24、e, adipose tissue,overexpression in renal cell carcinoma, breast and prostate cancer,high affinity for glucose and sensitive to insulin,high affinity for fructose,GLUT8,testis, adrenal gland, liver, spleen and lung.,overexpression in multiple myeloma,GLUT12,overexpression in breast cancer,heart, sma
25、ll intestine, skeletal muscle,Factors regulating expression of GLUTs, HK2, PFK1, PKM2,1. hypoxia,2. oncogene and tumor supressor gene,C-myc,p53,3. growth factors,EGF,4. hormones,estrogen,hypoxia-inducible factor-1, HIF-1,HIF-1,HIF-1,stable,prolyl hydroxylases (PHDs),hydroxylation,O2,+,transcription
26、of target genes,GLUT1,GLUT3,HK2,PDK1,LDHA,PKM2,hypoxia,SCI: Science Citation Index,Institute for Scientific Information,3500,Impact factor,Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme,The Journal of experimental medicine, 2011,gliobl
27、astoma multiforme:,the most common and lethal of all primary human central nervous system tumors,resistant to radiation and chemotherapy, and highly invasive,threefold increase in glycolysis relative to normal brain,High expression of HK2 in GBM and is related to poor prognosis,WHY?,HK2 provides a survival advantage to GBM cells?,How does HK2 promote cell growth and inhibit aopotosis? By reverting aerobic glycolysis to OXPHOS-dependent glucose metabolism?,
