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
Background:As a rate-limiting enzyme of glycolysis,pyruvate kinase muscle isozyme M2(PKM2)participates in tumor metabolism and growth.The regulatory network of PKM2 in cancer is complex and has not been fully studied ...Background:As a rate-limiting enzyme of glycolysis,pyruvate kinase muscle isozyme M2(PKM2)participates in tumor metabolism and growth.The regulatory network of PKM2 in cancer is complex and has not been fully studied in bladder cancer.The 5-methylcytidine(m5C)modification in PKM2 mRNA might participate in the pathogenesis of bladder cancer and need to be further clarified.This study aimed to investigate the biological function and regulatory mechanism of PKM2 in bladder cancer.Methods:The expression of PKM2 and Aly/REF export factor(ALYREF)was measured by Western blotting,qRT-PCR,and immunohistochemistry.The bioprocesses of bladder cancer cells were demonstrated by a series of experiments in vitro and in vivo.RNA immunoprecipitation,RNA-sequencing,and dualluciferase reporter assays were conducted to explore the potential regulatory mechanisms of PKM2 in bladder cancer.Results:In bladder cancer,we first demonstrated that ALYREF stabilized PKM2 mRNA and bound to its m5C sites in 3′-untranslated regions.Overexpression of ALYREF promoted bladder cancer cell proliferation by PKM2-mediated glycolysis.Furthermore,high expression of PKM2 and ALYREF predicted poor survival in bladder cancer patients.Finally,we found that hypoxia-inducible factor-1alpha(HIF-1α)indirectly up-regulated the expression of PKM2 by activating ALYREF in addition to activating its transcription directly.Conclusions:The m5C modification in PKM2 mRNA in the HIF-1α/ALYREF/PKM2 axis may promote the glucose metabolism of bladder cancer,providing a new promising therapeutic target for bladder cancer.展开更多
Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidati...Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.展开更多
The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells by...The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for thera- peutic interventions in various cancer types.展开更多
A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch betw...A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2: MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth.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supported by grants from the National Natural Science Foundation of China(81602235,81772711)the“333”project of Jiangsu Province(LGY2018055,LGY2016002)+2 种基金Key Provincial Talents Program of Jiangsu Province(ZDRCA2016006)the Priority Academic Program Development of Jiangsu Higher Education Institutions(JX10231801)the Provincial Initiative Program for Excellency Disciplines of Jiangsu Province(BE2016791).
文摘Background:As a rate-limiting enzyme of glycolysis,pyruvate kinase muscle isozyme M2(PKM2)participates in tumor metabolism and growth.The regulatory network of PKM2 in cancer is complex and has not been fully studied in bladder cancer.The 5-methylcytidine(m5C)modification in PKM2 mRNA might participate in the pathogenesis of bladder cancer and need to be further clarified.This study aimed to investigate the biological function and regulatory mechanism of PKM2 in bladder cancer.Methods:The expression of PKM2 and Aly/REF export factor(ALYREF)was measured by Western blotting,qRT-PCR,and immunohistochemistry.The bioprocesses of bladder cancer cells were demonstrated by a series of experiments in vitro and in vivo.RNA immunoprecipitation,RNA-sequencing,and dualluciferase reporter assays were conducted to explore the potential regulatory mechanisms of PKM2 in bladder cancer.Results:In bladder cancer,we first demonstrated that ALYREF stabilized PKM2 mRNA and bound to its m5C sites in 3′-untranslated regions.Overexpression of ALYREF promoted bladder cancer cell proliferation by PKM2-mediated glycolysis.Furthermore,high expression of PKM2 and ALYREF predicted poor survival in bladder cancer patients.Finally,we found that hypoxia-inducible factor-1alpha(HIF-1α)indirectly up-regulated the expression of PKM2 by activating ALYREF in addition to activating its transcription directly.Conclusions:The m5C modification in PKM2 mRNA in the HIF-1α/ALYREF/PKM2 axis may promote the glucose metabolism of bladder cancer,providing a new promising therapeutic target for bladder cancer.
文摘Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.
文摘The tricarboxylic acid （TCA） cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance require- ments. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for thera- peutic interventions in various cancer types.
基金Ministry of Science and Technology of the People's Republic of China (2017YFA0503404 and 2016YFC1304803)the National Natural Science Foundation of China (Grant Nos. 31625014, 31621063 and 31830040).
文摘A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2: MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth.
