共查询到20条相似文献,搜索用时 20 毫秒
1.
Pyruvate dehydrogenase kinase (PDK) can regulate the catalytic activity of pyruvate decarboxylation oxidation via the mitochondrial pyruvate dehydrogenase complex, and it further links glycolysis with the tricarboxylic acid cycle and ATP generation. This review seeks to elucidate the regulation of PDK activity in different species, mainly mammals, and the role of PDK inhibitors in preventing increased blood glucose, reducing injury caused by myocardial ischemia, and inducing apoptosis of tumor cells. Regulations of PDKs expression or activity represent a very promising approach for treatment of metabolic diseases including diabetes, heart failure, and cancer. The future research and development could be more focused on the biochemical understanding of the diseases, which would help understand the cellular energy metabolism and its regulation by pharmacological effectors of PDKs. 相似文献
2.
Elisa Carra Federica Barbieri Daniela Marubbi Alessandra Pattarozzi Roberto E. Favoni Tullio Florio Antonio Daga 《Cell cycle (Georgetown, Tex.)》2013,12(3):491-500
Glioblastomas are grade IV brain tumors characterized by high aggressiveness and invasiveness, giving patients a poor prognosis. We investigated the effects of the multi-kinase inhibitor sorafenib on six cultures isolated from human glioblastomas and maintained in tumor initiating cells-enriching conditions. These cell subpopulations are thought to be responsible for tumor recurrence and radio- and chemo-resistance, representing the perfect target for glioblastoma therapy. Sorafenib reduces proliferation of glioblastoma cultures, and this effect depends, at least in part, on the inhibition of PI3K/Akt and MAPK pathways, both involved in gliomagenesis. Sorafenib significantly induces apoptosis/cell death via downregulation of the survival factor Mcl-1. We provide evidence that sorafenib has a selective action on glioblastoma stem cells, causing enrichment of cultures in differentiated cells, downregulation of the expression of stemness markers required to maintain malignancy (nestin, Olig2 and Sox2) and reducing cell clonogenic ability in vitro and tumorigenic potential in vivo. The selectivity of sorafenib effects on glioblastoma stem cells is confirmed by the lower sensitivity of glioblastoma cultures after differentiation as compared with the undifferentiated counterpart. Since current GBM therapy enriches the tumor in cancer stem cells, the evidence of a selective action of sorafenib on these cells is therapeutically relevant, even if, so far, results from first phase II clinical trials did not demonstrate its efficacy. 相似文献
3.
Mosca E Barcella M Alfieri R Bevilacqua A Canti G Milanesi L 《Biotechnology advances》2012,30(1):131-141
Cancer has been proposed as an example of systems biology disease or network disease. Accordingly, tumor cells differ from their normal counterparts more in terms of intracellular network dynamics than single markers. Here we shall focus on a recently recognized hallmark of cancer, the deregulation of cellular energetics. The constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been confirmed as an essential step toward cell transformation. We will consider how the effects of Akt activation are connected with cell metabolism; more precisely, we will review existing metabolic models and discuss the current knowledge available to construct a kinetic model of the most relevant metabolic processes regulated by the PI3K/Akt pathway. The model will enable a systems biology approach to predict the metabolic targets that may inhibit cell growth under hyper activation of Akt. 相似文献
4.
5.
Panpan Chen Qianbin Zhang Huizhen Zhang Yue Gao Yanying Zhou Yixin Chen Lihuan Guan Tingying Jiao Yingyuan Zhao Min Huang Huichang Bi 《Journal of cellular physiology》2021,236(2):958-970
Cellular senescence, a state of growth arrest, is involved in various age‐related diseases. We previously found that carnitine palmitoyltransferase 1C (CPT1C) is a key regulator of cancer cell proliferation and senescence, but it is unclear whether CPT1C plays a similar role in normal cells. Therefore, this study aimed to investigate the role of CPT1C in cellular proliferation and senescence of human embryonic lung MRC‐5 fibroblasts and the involved mechanisms. The results showed that CPT1C could reverse the cellular senescence of MRC‐5 fibroblasts, as evidenced by reduced senescence‐associated β‐galactosidase activity, downregulated messenger RNA (mRNA) expression of senescence‐associated secretory phenotype factors, and enhanced bromodeoxyuridine incorporation. Lipidomics analysis further revealed that CPT1C gain‐of‐function reduced lipid accumulation and reversed abnormal metabolic reprogramming of lipids in late MRC‐5 cells. Oil Red O staining and Nile red fluorescence also indicated significant reduction of lipid accumulation after CPT1C gain‐of‐function. Consequently, CPT1C gain‐of‐function significantly reversed mitochondrial dysfunction, as evaluated by increased adenosine triphosphate synthesis and mitochondrial transmembrane potential, decreased radical oxygen species, upregulated respiratory capacity and mRNA expression of genes related to mitochondrial function. In summary, CPT1C plays a vital role in MRC‐5 cellular proliferation and can reverse MRC‐5 cellular senescence through the regulation of lipid metabolism and mitochondrial function, which supports the role of CPT1C as a novel target for intervention into cellular proliferation and senescence and suggests CPT1C as a new strategy for antiaging. 相似文献
6.
A major metabolic aberration associated with cancer is a change in glucose metabolism. Isoform selection of the glycolytic enzyme pyruvate kinase has been implicated in the metabolic phenotype of cancer cells, and specific pyruvate kinase isoforms have been suggested to support divergent energetic and biosynthetic requirements of cells in tumors and normal tissues. PKM2 isoform expression has been closely linked to embryogenesis, tissue repair, and cancer. In contrast, forced expression of the PKM1 isoform has been associated with reduced tumor cell proliferation. Here, we discuss the role that PKM2 plays in cells and provide a historical perspective for how the study of PKM2 has contributed to understanding cancer metabolism. We also review recent studies that raise important questions with regard to the role of PKM2 in both normal and cancer cell metabolism. 相似文献
7.
Glioblastoma is the most common brain tumor that causes significant mortality annually. Limitations of the current therapeutic
regimens warrant development of new techniques and treatment strategies in orthotopic animal model for better management of
this devastating brain cancer. There are only a few experimental orthotopic models of glioblastoma for pre-clinical testing.
In the present investigation, we successfully implanted rat C6 cells via intracranial stereotaxic cannulation in adult Sprague-Dawley
rats for development and histoimmunopathological characterization of an advanced orthotopic glioblastoma allograft model,
which could be useful for investigating the course of glioblastoma development as well as for testing efficacy of new therapeutic
agents. The orthotopic glioblastoma allograft was generated by intracerebral injection of rat C6 cells through a guide-cannula
system and after 21 post-inoculation days the brain tumor was characterized by histoimmunopathological experiments. Histological
staining and immunofluorescent labelings for TERT, VEGF, Bcl-2, survivin, XIAP, and GFAP revealed the distinct characteristics
of glioblastoma in C6 allograft, which could be useful as a target for treatment with emerging new therapeutic agents. Our
investigation indicated the successful development of intracranial cannulated orthotopic glioblastoma allograft in adult Sprague-Dawley
rats, making it as a useful animal model of glioblastoma for pre-clinical evaluation of various therapeutic strategies for
the management of glioblastoma.
Special issue in honor of Naren Banik. 相似文献
8.
Michael C. Oh Joseph M. Kim Michael Safaee Gurvinder Kaur Matthew Z. Sun Rajwant Kaur Anna Celli Theodora M. Mauro Andrew T. Parsa 《PloS one》2012,7(10)
Glioblastoma multiforme is the most malignant type of primary brain tumor with a poor prognosis. These tumors consist of a heterogeneous population of malignant cells, including well-differentiated tumor cells and less differentiated cells with stem cell properties. These cancer stem cells, known as brain tumor initiating cells, likely contribute to glioma recurrence, as they are highly invasive, mobile, resistant to radiation and chemotherapy, and have the capacity to self-renew. Glioblastoma tumor cells release excitotoxic levels of glutamate, which may be a key process in the death of peritumoral neurons, formation of necrosis, local inflammation, and glioma-related seizures. Moreover, elevated glutamate levels in the tumor may act in paracrine and autocrine manner to activate glutamate receptors on glioblastoma tumor cells, resulting in proliferation and invasion. Using a previously described culturing condition that selectively promotes the growth of brain tumor initiating cells, which express the stem cell markers nestin and SOX-2, we characterize the expression of α-amino-3-hydroxy-5-methyl-4-isozolepropionic acid (AMPA)-type glutamate receptor subunits in brain tumor initiating cells derived from glioblastomas. Here we show for the first time that glioblastoma brain tumor initiating cells express high concentrations of functional calcium-permeable AMPA receptors, compared to the differentiated tumor cultures consisting of non-stem cells. Up-regulated calcium-permeable AMPA receptor expression was confirmed by immunoblotting, immunocytochemistry, and intracellular calcium imaging in response to specific agonists. Our findings raise the possibility that glutamate secretion in the GBM tumor microenvironment may stimulate brain tumor derived cancer stem cells. 相似文献
9.
Kamil Makowski Paula Mera David Paredes Laura Herrero Xavier Ariza Guillermina Asins Fausto G. Hegardt Jordi García Dolors Serra 《Chirality》2013,25(5):281-287
C75 is a synthetic compound described as having antitumoral properties. It produces hypophagia and weight loss in rodents, limiting its use in cancer therapy but identifying it as a potential anti‐obesity drug. C75 is a fatty acid synthase (FAS) inhibitor and, through its coenzyme A (CoA) derivative, it acts as a carnitine palmitoyltransferase (CPT) 1 inhibitor. Racemic mixtures of C75 have been used in all the previous studies; however, the potential different biological activities of C75 enantiomers have not been examined yet. To address this question we synthesized the two C75 enantiomers separately. Our results showed that (?)‐C75 inhibits FAS activity in vitro and has a cytotoxic effect on tumor cell lines, without affecting food consumption. (+)‐C75 inhibits CPT1 and its administration produces anorexia, suggesting that central inhibition of CPT1 is essential for the anorectic effect of C75. The differential activity of C75 enantiomers may lead to the development of potential new specific drugs for cancer and obesity. Chirality 25:281–287, 2013. © 2013 Wiley Periodicals, Inc. 相似文献
10.
Philippe Marchetti Anne Trinh Raeeka Khamari Jerome Kluza 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(4):999-1005
Background
Besides its influence on survival, growth, proliferation, invasion and metastasis, cancer cell metabolism also greatly influences the cellular responses to molecular-targeted therapies.Scope of the review
To review the recent advances in elucidating the metabolic effects of BRAF and MEK inhibitors (clinical inhibitors of the MAPK/ERK pathway) in melanoma and discuss the underlying mechanisms involved in the way metabolism can influence melanoma cell death and resistance to BRAF and MEK inhibitors. We also underlined the therapeutic perspectives in terms of innovative drug combinations.Major conclusion
BRAF and MEK inhibitors inhibit aerobic glycolysis and induce high levels of metabolic stress leading to effective cell death by apoptosis in BRAF-mutated cancer cells. An increase in mitochondrial metabolism is required to survive to MAPK/ERK pathway inhibitors and the sub-population of cells that survives to these inhibitors are characterized by mitochondrial OXPHOS phenotype. Consequently, mitochondrial inhibition could be combined with oncogenic “drivers” inhibitors of the MAPK/ERK pathway for improving the efficacy of molecular-targeted therapy.General significance
Metabolism is a key component of the melanoma response to BRAF and/or MEK inhibitors. Mitochondrial targeting may offer novel therapeutic approaches to overwhelm the mitochondrial addiction that limits the efficacy of BRAF and/or MEK inhibitors. These therapeutic approaches might be quickly applicable to the clinical situation. 相似文献11.
Lin Wang Ziru Yu Shuyue Ren Junke Song Jinhua Wang Guanhua Du 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(10):2281-2292
Background
Metabolic reprogramming and hypoxia contribute to the resistance of conventional chemotherapeutic drugs in kinds of cancers. In this study, we investigated the effect of dihydrotanshinone I (DHTS) on reversing dysregulated metabolism of glucose and fatty acid in colon cancer and elucidated its mechanism of action.Methods
Cell viability was determined by MTT assay. Oxidative phosphorylation, glycolysis, and mitochondrial fuel oxidation were assessed by Mito stress test, glycolysis stress test, and mito fuel flex test, respectively. Anti-cancer activity of DHTS in vivo was evaluated in Colon cancer xenograft. Hexokinase activity and free fatty acid (FFA) content were assessed using respective Commercial kits. Gene expression patterns were determined by performing DNA microarray analysis and real-time PCR. Protein expression was assessed using immunoblotting and immunohistochemistry.Results
DHTS showed similar cytotoxicity against colon cancer cells under hypoxia and normoxia. DHTS decreased the efficiency of glucose and FA as mitochondrial fuels in HCT116 cells, which efficiently reversed by VO-OHpic trihydrate. DHTS reduced hexokinase activity and free fatty acid (FFA) content in tumor tissue of xenograft model of colon cancer. Gene expression patterns in metabolic pathways were dramatically differential between model and treatment group. Increases in PTEN and a substantial decrease in the expression of SIRT3, HIF1α, p-AKT, HKII, p-MTOR, RHEB, and p-ACC were detected.Conclusions
DHTS reversed metabolic reprogramming in colon cancer through PTEN/AKT/HIF1α-mediated signal pathway.General significance
The study is the first to report the reverse of metabolic reprogramming by DHTS in colon cancer. Meantime, SIRT3/PTEN/AKT/HIF1α mediated signal pathway plays a critical role during this process. 相似文献12.
N Sanchez-Macedo J Feng B Faubert N Chang A Elia E J Rushing K Tsuchihara D Bungard S L Berger R G Jones T W Mak K Zaugg 《Cell death and differentiation》2013,20(4):659-668
Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors. 相似文献
13.
Michal Grzmil Brian A. Hemmings 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(3):476-483
Despite the variety of modern therapies against human brain cancer, in its most aggressive form of glioblastoma multiforme (GBM) it is a still deadly disease with a median survival of approximately 1 year. Over the past 2 decades, molecular profiling of low- and high-grade malignant brain tumours has led to the identification and molecular characterisation of mechanisms leading to brain cancer development, maintenance and progression. Genetic alterations occurring during gliomagenesis lead to uncontrolled tumour growth stimulated by deregulated signal transduction pathways. The characterisation of hyperactivated signalling pathways has identified many potential molecular targets for therapeutic interference in human gliomas. Overexpressed or mutated and constitutively active kinases are attractive targets for low-molecular-weight inhibitors. Although the first attempts with mono-therapy using a single targeted kinase inhibitor were not satisfactory, recent studies based on the simultaneous targeting of several core hyperactivated pathways show great promise for the development of novel therapeutic approaches. This review focuses on genetic alterations leading to the activation of key deregulated pathways in human gliomas. 相似文献
14.
15.
Nadia A. Atai Nynke A. Renkema-Mills Joost Bosman Nadja Schmidt Denise Rijkeboer Wikky Tigchelaar Klazien S. Bosch Dirk Troost Ard Jonker Fonnet E. Bleeker Hrvoje Miletic Rolf Bjerkvig Philip C. De Witt Hamer Cornelis J. F. Van Noorden 《The journal of histochemistry and cytochemistry》2011,59(5):489-503
The somatic IDH1R132 mutation in the isocitrate dehydrogenase 1 gene occurs in high frequency in glioma and in lower frequency in acute myeloid leukemia and thyroid cancer but not in other types of cancer. The mutation causes reduced NADPH production capacity in glioblastoma by 40% and is associated with prolonged patient survival. NADPH is a major reducing compound in cells that is essential for detoxification and may be involved in resistance of glioblastoma to treatment. IDH has never been considered important in NADPH production. Therefore, the authors investigated NADPH-producing dehydrogenases using in silico analysis of human cancer gene expression microarray data sets and metabolic mapping of human and rodent tissues to determine the role of IDH in total NADPH production. Expression of most NADPH-producing dehydrogenase genes was not elevated in 34 cancer data sets except for IDH1 in glioma and thyroid cancer, indicating an association with the IDH1 mutation. IDH activity was the main provider of NADPH in human normal brain and glioblastoma, but its role was modest in NADPH production in rodent brain and other tissues. It is concluded that rodents are a poor model to study consequences of the IDH1R132 mutation in glioblastoma. 相似文献
16.
Polly J. Phillips‐Mason Harpreet Kaur Susan M. Burden‐Gulley Sonya E.L. Craig Susann M. Brady‐Kalnay 《Journal of cellular biochemistry》2011,112(1):39-48
The receptor protein tyrosine phosphatase PTPµ has a cell‐adhesion molecule‐like extracellular segment and a catalytically active intracellular segment. This structure gives PTPµ the ability to transduce signals in response to cell–cell adhesion. Full‐length PTPµ is down‐regulated in glioma cells by proteolysis which is linked to increased migration of these cells in the brain. To gain insight into the substrates PTPµ may be dephosphorylating to suppress glioma cell migration, we used a substrate trapping method to identify PTPµ substrates in tumor cell lines. We identified both PKCδ and PLCγ1 as PTPµ substrates. As PLCγ1 activation is linked to increased invasion of cancer cells, we set out to determine whether PTPµ may be upstream of PLCγ1 in regulating glioma cell migration. We conducted brain slice assays using U87‐MG human glioma cells in which PTPµ expression was reduced by shRNA to induce migration. Treatment of the same cells with PTPµ shRNA and a PLCγ1 inhibitor prevented migration of the cells within the brain slice. These data suggest that PLCγ1 is downstream of PTPµ and that dephosphorylation of PLCγ1 is likely to be a major pathway through which PTPµ suppresses glioma cell migration. J. Cell. Biochem. 112: 39–48, 2011. © 2010 Wiley‐Liss, Inc. 相似文献
17.
Enrico Desideri Rolando Vegliante Simone Cardaci Ridvan Nepravishta Maurizio Paci Maria Rosa Ciriolo 《Autophagy》2014,10(9):1652-1665
Increased glycolytic flux is a common feature of many cancer cells, which have adapted their metabolism to maximize glucose incorporation and catabolism to generate ATP and substrates for biosynthetic reactions. Indeed, glycolysis allows a rapid production of ATP and provides metabolic intermediates required for cancer cells growth. Moreover, it makes cancer cells less sensitive to fluctuations of oxygen tension, a condition usually occurring in a newly established tumor environment. Here, we provide evidence for a dual role of MAPK14 in driving a rearrangement of glucose metabolism that contributes to limiting reactive oxygen species (ROS) production and autophagy activation in condition of nutrient deprivation. We demonstrate that MAPK14 is phosphoactivated during nutrient deprivation and affects glucose metabolism at 2 different levels: on the one hand, it increases SLC2A3 mRNA and protein levels, resulting in a higher incorporation of glucose within the cell. This event involves the MAPK14-mediated enhancement of HIF1A protein stability. On the other hand, MAPK14 mediates a metabolic shift from glycolysis to the pentose phosphate pathway (PPP) through the modulation of PFKFB3 (6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase 3) degradation by the proteasome. This event requires the presence of 2 distinct degradation sequences, KEN box and DSG motif Ser273, which are recognized by 2 different E3 ligase complexes. The mutation of either motif increases PFKFB3 resistance to starvation-induced degradation. The MAPK14-driven metabolic reprogramming sustains the production of NADPH, an important cofactor for many reduction reactions and for the maintenance of the proper intracellular redox environment, resulting in reduced levels of ROS. The final effect is a reduced activation of autophagy and an increased resistance to nutrient deprivation. 相似文献
18.
19.
PPAR delta is the only member in the PPAR subfamily of nuclear receptors that is not a target of current drugs. Animal studies demonstrate PPAR delta activation exerts many favorable effects, including reducing weight gain, increasing skeletal muscle metabolic rate and endurance, improving insulin sensitivity and cardiovascular function and suppressing atherogenic inflammation. These activities stem largely from the ability of PPAR delta to control energy balance, reduce fat burden and protect against lipotoxicity caused by ectopic lipid deposition. Therefore, PPAR delta represents a novel therapeutic target and the development of PPAR delta gonists/modulators may be useful for treating the whole spectrum of metabolic syndrome. 相似文献
20.
Ya-Nan Xue Bing-Bing Yu Jiu-Ling Li Rui Guo Li-Chao Zhang Lian-Kun Sun Ya-Nan Liu Yang Li 《Experimental cell research》2019,374(1):249-258
Many cell death regulators physically or functionally interact with metabolic enzymes. These interactions provide insights into mechanisms of anticancer treatments from the perspective of tumor cell metabolism and apoptosis. Recent studies have shown that zinc and p53 not only induce tumor cell apoptosis, but also regulate tumor cell metabolism. However, the underlying mechanism is complex and remains unclear, making further research imperative to provide clues for future cancer treatments. In this study, we found that hexokinase 2 (HK2), which has dual metabolic and apoptotic functions, is downstream of zinc and p53 in both prostate cancer patient tissue and prostate cancer cell lines. Notably, the mitochondrial location of HK2 is crucial for its function. We demonstrate that zinc and p53 disrupt mitochondrial binding of HK2 in prostate cancer cells by phosphorylating VDAC1, which is mediated by protein kinase B (Akt) inhibition and glycogen synthase kinase 3β (GSK3β) activation. In addition, we found that zinc combined with p53 significantly inhibited tumor growth in a prostate cancer cell xenograft model. Therefore, interference of the mitochondrial localization of HK2 by zinc and p53 may provide a new treatment approach for cancer. 相似文献