Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence worldwide.Multiple efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibito...Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence worldwide.Multiple efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibitors,immune based therapies and combination of chemotherapy.However,limitations exist in current strategies including chemoresistance for instance.Tumor initiation and progression is driven by reprogramming of metabolism,in particular during HCC development.Recently,metabolic associated fatty liver disease(MAFLD),a reappraisal of new nomenclature for nonalcoholic fatty liver disease(NAFLD),indicates growing appreciation of metabolism in the pathogenesis of liver disease,including HCC,thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment.In this review,we introduce directions by highlighting the metabolic targets in glucose,fatty acid,amino acid and glutamine metabolism,which are suitable for HCC pharmaceutical intervention.We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment.Furthermore,opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.展开更多
Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and suppor...Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phos- phate pathway （PPP） is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxi- dative branch and produces a reduced form of nico- tinamide adenine dinucleotide phosphate （NADPH）, an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell pro- liferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous fac- tors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.展开更多
Glucose-6-phosphate dehydrogenase （G6PDH, E.C. 1.1.1.49） and 6-phosphogluconate dehydrogenase （6PGDH, EC 1.1.1.44） are both key enzymes of the pentose phosphate pathway （PPP）. The OsG6PDH1 and Os6PGDH1 genes enc...Glucose-6-phosphate dehydrogenase （G6PDH, E.C. 1.1.1.49） and 6-phosphogluconate dehydrogenase （6PGDH, EC 1.1.1.44） are both key enzymes of the pentose phosphate pathway （PPP）. The OsG6PDH1 and Os6PGDH1 genes encoding cytosolic G6PDH and cytosolic 6PGDH were Isolated from rice （Oryza sativa L.）. We have shown that Os6PGDH1 gene was up-regulated by salt stress. Here we reported the isolation and characterization of Os6PGDH2 from rice, which encode the plastidic counterpart of 6PGDH. Genomic organization analysis indicated that OsG6PDH1 and OsG6PDH2 genes contain multiple introns, whereas two Os6PGDH1 and Os6PGDH2 genes have no introns in their translated regions. In a step towards understanding the functions of the pentose phosphate pathway in plants in response to various abiotic stresses, the expressions of four genes in the rice seedlings treated by drought, cold, high salinity and abscisic acid （ABA） were investigated. The results show that OsG6PDH1 and OsG6PDH2 are not markedly regulated by the abiotic stresses detected. However, the transcript levels of both Os6PGDH1 and Os6PGDH2 are up-regulated in rice seedlings under drought, cold, high salinity and ABA treatments. Meanwhile, the enzyme activities of G6PDH and 6PGDH in the rice seedlings treated by various abiotic stresses were Investigated. Like the mRNA expression patterns, G6PDH activity remains constant but the 6PGDH Increases steadily during the treatments. Taken together, we suggest that the pentose phosphate pathway may play an important role in rice responses to abiotic stresses and the second key enzyme of PPP, 6PGDH, may function as a regulator controlling the efficiency of the pathway under abiotic stresses.展开更多
Changes in main biochemical respiratory pathways in dormant nectarine floral buds were studied with nectarine trees （Prunus persica.var, nectariana cv. Shuguang） in order to determine the function of respiration in ...Changes in main biochemical respiratory pathways in dormant nectarine floral buds were studied with nectarine trees （Prunus persica.var, nectariana cv. Shuguang） in order to determine the function of respiration in dormancy release. Oxygen-electrode system and respiratory inhibitors were used to measure total respiratory rates and rates of respiratory pathways. Results showed that chilling deficiency blocked the transition of respiratory mode, and made buds stay in a state of high level pentose phosphate pathway （PPP） and low level tricarboxylie acid cycle （TCA）. The decline of PPP and activation of TCA occurred synchronously with the release of dormancy. In addition, the inhibition of PPP stimulated a respiration increase related with TCA. It could be concluded that the function of PPP activation in dormancy release might be limited and PPP declination inducing TCA activation might be part of respiration mode transition mechanism during bud sprouting.展开更多
Cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT)plays a key role in antioxidant defense by mediating cystine uptake,promoting glutathione synthesis,and maintaining cell surviva...Cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT)plays a key role in antioxidant defense by mediating cystine uptake,promoting glutathione synthesis,and maintaining cell survival under oxidative stress conditions.Recent studies showed that,to prevent toxic buildup of highly insoluble cystine inside cells,cancer cells with high expression of SLC7A11(SLC7A11high)are forced to quickly reduce cystine to more soluble cysteine,which requires substantial NADPH supply from the glucose-pentose phosphate pathway(PPP)route,thereby inducing glucose-and PPP-dependency in SLC7A11high cancer cells.Limiting glucose supply to SLC7A11high cancer cells results in significant NADPH“debt”,redox“bankruptcy”,and subsequent cell death.This review summarizes our current understanding of NADPH-generating and-consuming pathways,discusses the opposing role of SLC7A11 in protecting cells from oxidative stresseinduced cell death such as ferroptosis but promoting glucose starvationeinduced cell death,and proposes the concept that SLC7A11-mediated cystine uptake acts as a double-edged sword in cellular redox regulation.A detailed understanding of SLC7A11 in redox biology may identify metabolic vulnerabilities in SLC7A11high cancer for therapeutic targeting.展开更多
Transketolase （TK）, a thiamine diphosphate （ThDP）-dependent enzyme, catalyzes several key reactions of nonoxidative branch of pentose phosphate pathway. TK is a homodimer with two active sites that locate at the i...Transketolase （TK）, a thiamine diphosphate （ThDP）-dependent enzyme, catalyzes several key reactions of nonoxidative branch of pentose phosphate pathway. TK is a homodimer with two active sites that locate at the interface between the contacting monomers. Both ThDP and bivalent cations are strictly needed for TK activation, just like that for all ThDPdependent enzymes. TK exists in all organisms that have been investigated. Up to now, one TK gene （TKT） and two transketolase-like genes （TKTL1 and TKTL2） have been identified in human genome. TKTL1 is reported to play a pivotal role in carcinogenesis and may have important implications in the nutrition and future treatment of patients with cancer. Research- ers have found TK variants and reduced activities of TK enzyme in patients with neurodegenerative diseases, diabetes, and cancer. Recent studies indicated TK as a novel role in the prevention and therapy of these diseases.展开更多
基金supported by the National Natural Science Foundation of China(No.82070883)Scientific Research Foundation for high-level faculty,China Pharmaceutical University(Nanjing,China)。
文摘Hepatocellular carcinoma(HCC)is an aggressive human cancer with increasing incidence worldwide.Multiple efforts have been made to explore pharmaceutical therapies to treat HCC,such as targeted tyrosine kinase inhibitors,immune based therapies and combination of chemotherapy.However,limitations exist in current strategies including chemoresistance for instance.Tumor initiation and progression is driven by reprogramming of metabolism,in particular during HCC development.Recently,metabolic associated fatty liver disease(MAFLD),a reappraisal of new nomenclature for nonalcoholic fatty liver disease(NAFLD),indicates growing appreciation of metabolism in the pathogenesis of liver disease,including HCC,thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment.In this review,we introduce directions by highlighting the metabolic targets in glucose,fatty acid,amino acid and glutamine metabolism,which are suitable for HCC pharmaceutical intervention.We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment.Furthermore,opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.
基金We apologize to those authors whose excellent work could not be cited due to space constraints. This work was supported by the Start-Up Package Fund from Tsinghua University to J.P. and the grant （Grants No. 2010CB912804 and 31030046 to WM） from National Natural Science Foundation of China.
文摘Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the pro- motion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phos- phate pathway （PPP） is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxi- dative branch and produces a reduced form of nico- tinamide adenine dinucleotide phosphate （NADPH）, an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell pro- liferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous fac- tors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.
基金Suported by the Ph.D Foundation Program from the Ministry of Education （20050307013）, the National Natural Science Foundation of China （30470921）, the Jiangsu Provincial Natural Science Foundation of China （BK2005090） and the Changjiang Scholars and Innovative Research Team in University （PCSIRT）.The nucleotide sequences reported in this paper have been deposited in GenBank under the accession numbers AY078072, AY339367, AF486280 and AY278362, respectively,
文摘Glucose-6-phosphate dehydrogenase （G6PDH, E.C. 1.1.1.49） and 6-phosphogluconate dehydrogenase （6PGDH, EC 1.1.1.44） are both key enzymes of the pentose phosphate pathway （PPP）. The OsG6PDH1 and Os6PGDH1 genes encoding cytosolic G6PDH and cytosolic 6PGDH were Isolated from rice （Oryza sativa L.）. We have shown that Os6PGDH1 gene was up-regulated by salt stress. Here we reported the isolation and characterization of Os6PGDH2 from rice, which encode the plastidic counterpart of 6PGDH. Genomic organization analysis indicated that OsG6PDH1 and OsG6PDH2 genes contain multiple introns, whereas two Os6PGDH1 and Os6PGDH2 genes have no introns in their translated regions. In a step towards understanding the functions of the pentose phosphate pathway in plants in response to various abiotic stresses, the expressions of four genes in the rice seedlings treated by drought, cold, high salinity and abscisic acid （ABA） were investigated. The results show that OsG6PDH1 and OsG6PDH2 are not markedly regulated by the abiotic stresses detected. However, the transcript levels of both Os6PGDH1 and Os6PGDH2 are up-regulated in rice seedlings under drought, cold, high salinity and ABA treatments. Meanwhile, the enzyme activities of G6PDH and 6PGDH in the rice seedlings treated by various abiotic stresses were Investigated. Like the mRNA expression patterns, G6PDH activity remains constant but the 6PGDH Increases steadily during the treatments. Taken together, we suggest that the pentose phosphate pathway may play an important role in rice responses to abiotic stresses and the second key enzyme of PPP, 6PGDH, may function as a regulator controlling the efficiency of the pathway under abiotic stresses.
基金supported by the National 863 Program of China(2005AA247041)Key Projects in the National Science and Technology Pillar Program during the 11th Five-Year Plan period,China(2006BAD07B06)
文摘Changes in main biochemical respiratory pathways in dormant nectarine floral buds were studied with nectarine trees （Prunus persica.var, nectariana cv. Shuguang） in order to determine the function of respiration in dormancy release. Oxygen-electrode system and respiratory inhibitors were used to measure total respiratory rates and rates of respiratory pathways. Results showed that chilling deficiency blocked the transition of respiratory mode, and made buds stay in a state of high level pentose phosphate pathway （PPP） and low level tricarboxylie acid cycle （TCA）. The decline of PPP and activation of TCA occurred synchronously with the release of dormancy. In addition, the inhibition of PPP stimulated a respiration increase related with TCA. It could be concluded that the function of PPP activation in dormancy release might be limited and PPP declination inducing TCA activation might be part of respiration mode transition mechanism during bud sprouting.
基金This work was supported by the Andrew Sabin Family Fellow Award from The University of Texas MD Anderson Cancer Center,KC180131 fromDepartment of Defense Kidney Cancer Research Program,R01CA181196 and R01CA244144 from the National Institutes of Health(to B.G.).
文摘Cystine/glutamate antiporter solute carrier family 7 member 11(SLC7A11;also known as xCT)plays a key role in antioxidant defense by mediating cystine uptake,promoting glutathione synthesis,and maintaining cell survival under oxidative stress conditions.Recent studies showed that,to prevent toxic buildup of highly insoluble cystine inside cells,cancer cells with high expression of SLC7A11(SLC7A11high)are forced to quickly reduce cystine to more soluble cysteine,which requires substantial NADPH supply from the glucose-pentose phosphate pathway(PPP)route,thereby inducing glucose-and PPP-dependency in SLC7A11high cancer cells.Limiting glucose supply to SLC7A11high cancer cells results in significant NADPH“debt”,redox“bankruptcy”,and subsequent cell death.This review summarizes our current understanding of NADPH-generating and-consuming pathways,discusses the opposing role of SLC7A11 in protecting cells from oxidative stresseinduced cell death such as ferroptosis but promoting glucose starvationeinduced cell death,and proposes the concept that SLC7A11-mediated cystine uptake acts as a double-edged sword in cellular redox regulation.A detailed understanding of SLC7A11 in redox biology may identify metabolic vulnerabilities in SLC7A11high cancer for therapeutic targeting.
基金the National Natural Science Foundation of China (No. 30870871).
文摘Transketolase （TK）, a thiamine diphosphate （ThDP）-dependent enzyme, catalyzes several key reactions of nonoxidative branch of pentose phosphate pathway. TK is a homodimer with two active sites that locate at the interface between the contacting monomers. Both ThDP and bivalent cations are strictly needed for TK activation, just like that for all ThDPdependent enzymes. TK exists in all organisms that have been investigated. Up to now, one TK gene （TKT） and two transketolase-like genes （TKTL1 and TKTL2） have been identified in human genome. TKTL1 is reported to play a pivotal role in carcinogenesis and may have important implications in the nutrition and future treatment of patients with cancer. Research- ers have found TK variants and reduced activities of TK enzyme in patients with neurodegenerative diseases, diabetes, and cancer. Recent studies indicated TK as a novel role in the prevention and therapy of these diseases.
