Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Certain lipophilic cations have been reported to display anticarcinoma activities because of their selective uptake and retention by mitochondria of cancer cells. Thus, these agents may comprise a unique class of agents directed against carcinoma. After screening more than 1000 lipophilic cations, we found that the monovalent lipophilic cation, 2,6-bis(4-amino-phenyl)-4-[4-(dimethylamino)phenyl]thiopyrylium chloride (AA1), displayed remarkable anticarcinoma activity both in vitro and in vivo. Unlike most other lipophilic cations, AA1 is stable and displays minimal light sensitivity. In vitro testing showed that AA1 was 10 times more toxic to the carcinoma cell line CX-1 than to the normal epithelial cell line CV-1. In vivo animal experiments showed that AA1 significantly prolonged the survival of mice implanted with tumors. For C57BL x DBA/2 F1 mice implanted with the mouse bladder carcinoma cell line, MB49, the treated:control ratio was 344%. For Swiss nu/nu mice implanted i.p. with the human melanoma cell line, LOX, the treated:control ratio was 341%. The most significant observation was obtained with Swiss nu/nu mice that were implanted i.p. with the human ovarian cell line, OVCAR-III. The treated:control ratio in this situation was greater than 450%. In all these tumor models, AA1 produced minimal toxicities. AA1 exhibited little inhibition of electron transport in isolated rat liver mitochondria; however, it inhibited mitochondrial ATPase with 50% inhibitory concentration of 6 microM. Compared with previously reported anticarcinoma lipophilic cations such as rhodamine 123 and dequalinium chloride, AA1 appeared to display more effective in vivo anticarcinoma activity. Thus, AA1 could be considered for further clinical development as a candidate for anticarcinoma chemotherapy.
Cancer Res 1994 Mar 15
PMID:AA1, a newly synthesized monovalent lipophilic cation, expresses potent in vivo antitumor activity. 813 49

The human retinoblastoma cell line Y79 has multiple copies of the MYCN gene and the DEAD box gene DDXI. Both genes have been mapped to chromosome band 2p24. A third gene, encoding the alpha-subunit of mitochondrial ATP synthase (ATPSA), is also amplified in Y79. Here we report that there are at least four human mitochondrial ATPSA-related genes located on four different chromosomes. The ATPSA gene that is amplified in Y79 originates from chromosome 18. In Y79, the amplified copies of both the ATPSA and the MYCN genes are located on a homogeneously staining region (HSR) at chromosome band Ip34.
Genes Chromosomes Cancer 1995 Sep
PMID:Mitochondrial ATP synthase alpha-subunit gene amplified in a retinoblastoma cell line maps to chromosome 18. 852 86

Antisense strategy has been used to inhibit the synthesis of the human ubiquitous mitochondrial creatine kinase (Mi-CK) in HeLa cells. Indeed, elevated levels of Mi-CK in the serum of some cancer patients seem to be an adverse pronostic indicator (for refs see Wallimann T and Hemmer W, Mol Cell Biochem 133/134: 193-220, 1994). A phosphorothioate oligonucleotide, complementary to the second intron-exon splice junction site of the human ubiquitous Mi-CK pre-mRNA was shown to inhibit Mi-CK synthesis by 80% without modifying F1-ATPase beta subunit expression or hampering HeLa cell growth. This inhibition was correlated to a decrease of the Mi-CK mRNA level that could be determined quantitatively after amplification of reverse transcription products (RT) in the presence of varying concentrations of internal standard competitors. This study also demonstrated that the Mi-CK mRNA copy number was much lower in HeLa cells than that of the cytosolic creatine kinase isoform, B-CK. The antisense-induced decrease in Mi-CK mRNA and protein level influenced neither the expression of B-CK which uses up the phosphocreatine produced by Mi-CK during the phosphocreatine shuttle, nor that of another nuclear encoded mitochondrial gene, the F1-ATPase subunit which provides ATP to Mi-CK. In conclusion, an elevated Mi-CK expression is not required for cancer cell growth and therefore, Mi-CK is not a significant limiting factor for the growth of the cancer cells which contain it. In addition, a decrease in Mi-CK synthesis does not induce a change in the expression of mitochondrial F1-ATPase which provides ATP to Mi-CK or in the expression of cytosolic B-CK which is involved together with Mi-CK in the phosphocreatine shuttle. Therefore, the use of the phosphocreatine shuttle as a process mandatory for the active growth of some cancer cells is questioned.
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PMID:Inhibition of ubiquitous mitochondrial creatine kinase expression in HeLa cells by an antisense oligodeoxynucleotide. 905 88

Cancer cells, despite growing aerobically, have the propension to utilize the glycolytic pathway as energy source. This biochemical phenotype is accompanied by a decreased content of mitochondria and, paradoxically, by enhanced transcription of nuclear and mitochondrial-encoded genes for the enzymes of oxidative phosphorylation (OXPHOS). The role of OXPHOS enzymes in normal and neoplastic cell growth has been studied in liver regeneration and human hepatocellular carcinoma. In early liver regeneration characterized by active mtDNA replication, a decrease in the content and activity of ATP synthase occurs while transcription of the ATPsyn beta nuclear gene is activated. Translation of ATP synthase subunits seems, on the contrary, to be less effective in this phase. In the second replicative phase of liver regeneration, the repression of ATPsyn beta translation is relieved and normal cell growth starts. In this replicative phase the recovery of the liver mass appears to be directly related to the recovery of the OXPHOS capacity. Mitochondria isolated from biopsies of human hepatocellular carcinoma exhibit a decreased rate of respiratory ATP synthesis (OXPHOS) and a decreased ATPase activity. The decline in the activity of the ATP synthase is found to be associated with a decreased content of the ATPsyn beta in the inner mitochondrial membrane. In neoplastic tissue the ATPase inhibitor protein (IF1) is overexpressed. This could contribute to prevent hydrolysis of glycolytic ATP in cancer cells. A peptide segment of IF1 (IF1-(42-58)-peptide), constructed by chemical synthesis, proved to be equally effective as IF1 in inhibiting the ATPase activity of the ATP synthase complex in the mitochondrial membrane deprived of IF1. The synthetic peptide might turn out to be a useful tool to develop immunological approaches for the control of neoplastic growth.
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PMID:Oxidative phosphorylation enzymes in normal and neoplastic cell growth. 938 98

Piceatannol is a stilbene phytochemical from the seeds of Euphorbia lagascae, previously identified as an antileukemic principle. Piceatannol is considered an inhibitor of several tyrosine kinases. We recently reported that resveratrol, another stilbene phytoalexin from grape seeds, was an inhibitor of ATP synthase. Here, we demonstrated that piceatannol potently inhibited the rat brain mitochondrial F0F1-ATPase activity in both solubilized and submitochondrial preparations (IC50 of 8-9 microM), while having relatively small effect on the Na(+), K(+)-ATPase activity of porcine cerebral cortex (no effect up to 7 microM). Piceatannol inhibited the ATPase activity of the purified rat liver F1 with IC50 of about 4 microM, while resveratrol was slightly less active (IC50 of about 14 microM). Our results indicate that piceatannol and resveratrol inhibit the F-type ATPase by targeting the F1 sector, which is located to the inner membrane of mitochondria and plasma membrane of normal endothelial cells and several cancer cell lines. This mechanism could potentially contribute to the multiple effects of these chemopreventive phytochemicals.
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PMID:Piceatannol, a stilbene phytochemical, inhibits mitochondrial F0F1-ATPase activity by targeting the F1 complex. 1042 14

To characterize the mechanisms governing the biogenesis of mitochondria in cancer, we studied the mitochondrial phenotype and the mechanisms controlling the expression of the beta subunit of the mitochondrial H(+)-ATP synthase (beta-F1-ATPase) gene in the rat FAO and AS30D hepatomas. When compared with normal adult rat liver, the relative cellular content of the mitochondrial beta-F1-ATPase and glutamate dehydrogenase, as well as of mitochondrial DNA, was severely reduced in both cell lines. A paradoxical increase in the cellular abundance of beta-F1-ATPase mRNA was observed in cancer cells. Run-on transcription assays and the estimation of mRNA half-lives revealed that the increased abundance of beta-F1-ATPase mRNA results from the stabilization of the transcript in cancer. In vitro translation assays revealed a specific inhibition of the synthesis of the beta-precursor when translation reactions were carried out in the presence of extracts derived from cancer cells. The inhibitory effect was recapitulated using an RNA chimera that contained the 3'-untranslated region of beta-F1-ATPase mRNA. Hepatoma extracts also contained an increased activity of the developmentally regulated translation-inhibitory proteins that bind the 3'-untranslated region of beta-F1-ATPase mRNA. The results indicate that the expression of this gene in hepatoma cells is controlled by the same mechanisms that regulate its expression in the liver during fetal development.
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PMID:A conserved mechanism for controlling the translation of beta-F1-ATPase mRNA between the fetal liver and cancer cells. 1070 18

Recently, a family of polyketide inhibitors of F(0)F(1)-ATPase, including apoptolidin, ossamycin, and oligomycin, were shown to be among the top 0.1% most cell line selective cytotoxic agents of 37, 000 molecules tested against the 60 human cancer cell lines of the National Cancer Institute. Many cancer cells maintain a high level of anaerobic carbon metabolism even in the presence of oxygen, a phenomenon that is historically known as the Warburg effect. A mechanism-based strategy to sensitize such cells to this class of potent small molecule cytotoxic agents is presented. These natural products inhibit oxidative phosphorylation by targeting the mitochondrial F(0)F(1) ATP synthase. Evaluation of gene expression profiles in a panel of leukemias revealed a strong correlation between the expression level of the gene encoding subunit 6 of the mitochondrial F(0)F(1) ATP synthase (known to be the binding site of members of this class of macrolides) and their sensitivity to these natural products. Within the same set of leukemia cell lines, comparably strong drug-gene correlations were also observed for the genes encoding two key enzymes involved in central carbon metabolism, pyruvate kinase, and aspartate aminotransferase. We propose a simple model in which the mitochondrial apoptotic pathway is activated in response to a shift in balance between aerobic and anaerobic ATP biosynthesis. Inhibitors of both lactate formation and carbon flux through the Embden-Meyerhof pathway significantly sensitized apoptolidin-resistant tumors to this drug. Nine different cell lines derived from human leukemias and melanomas, and colon, renal, central nervous system, and ovarian tumors are also sensitized to killing by apoptolidin.
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PMID:Understanding and exploiting the mechanistic basis for selectivity of polyketide inhibitors of F(0)F(1)-ATPase. 1112 Oct 76

Angiostatin blocks tumor angiogenesis in vivo, almost certainly through its demonstrated ability to block endothelial cell migration and proliferation. Although the mechanism of angiostatin action remains unknown, identification of F(1)-F(O) ATP synthase as the major angiostatin-binding site on the endothelial cell surface suggests that ATP metabolism may play a role in the angiostatin response. Previous studies noting the presence of F(1) ATP synthase subunits on endothelial cells and certain cancer cells did not determine whether this enzyme was functional in ATP synthesis. We now demonstrate that all components of the F(1) ATP synthase catalytic core are present on the endothelial cell surface, where they colocalize into discrete punctate structures. The surface-associated enzyme is active in ATP synthesis as shown by dual-label TLC and bioluminescence assays. Both ATP synthase and ATPase activities of the enzyme are inhibited by angiostatin as well as by antibodies directed against the alpha- and beta-subunits of ATP synthase in cell-based and biochemical assays. Our data suggest that angiostatin inhibits vascularization by suppression of endothelial-surface ATP metabolism, which, in turn, may regulate vascular physiology by established mechanisms. We now have shown that antibodies directed against subunits of ATP synthase exhibit endothelial cell-inhibitory activities comparable to that of angiostatin, indicating that these antibodies function as angiostatin mimetics.
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PMID:Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin. 1138 Nov 44

Mitochondrial H+-ATP synthase is required for cellular energy provision and for efficient execution of apoptosis. Almost one century ago, Otto Warburg proposed the hypothesis that mitochondrial function might be impaired in cancer cells. However, his hypothesis was never demonstrated in human carcinomas. In this study, we have analyzed the expression of the beta-catalytic subunit of the H+-ATP synthase (beta-F1-ATPase) of mitochondria in carcinomas of the human liver, kidney, and colon. We show that carcinogenesis in the liver involves a depletion of the cellular mitochondrial content, as revealed by reduced content of mitochondrial markers, whereas in kidney and colon carcinomas, it involves a selective repression of the expression of the beta-F1-ATPase concurrent with an increase in the expression of the glycolytic glyceraldehyde-3-phosphate dehydrogenase. Both mechanisms limit mitochondrial cellular activity in cancer, strongly supporting Warburg's hypothesis, and suggest a mechanism for the resistance and compromised apoptotic potential of tumor cells. Furthermore, we show that the metabolic state of the cell, as defined by a bioenergetic mitochondrial index relative to the cellular glycolytic potential, provides a signature of carcinogenesis of prognostic value in assessing the progression of colorectal carcinomas.
Cancer Res 2002 Nov 15
PMID:The bioenergetic signature of cancer: a marker of tumor progression. 1243 66

Extracellular ATP synthesis on human umbilical vein endothelial cells (HUVECs) was examined, and it was found that HUVECs possess high ATP synthesis activity on the cell surface. Extracellular ATP generation was detected within 5 s after addition of ADP and inorganic phosphate and reached a maximal level at 15 s. This type of ATP synthesis was almost completely inhibited by mitochondrial H(+)-ATP synthase inhibitors (e.g., efrapeptins, resveratrol, and piceatannol), which target the F(1) catalytic domain. Oligomycin and carbonyl cyanide m-chlorophenylhydrazone, but not potassium cyanide, also inhibited extracellular ATP synthesis on HUVECs, suggesting that cell surface ATP synthase employs the transmembrane electrochemical potential difference of protons to synthesize ATP as well as mitochondrial H(+)-ATP synthase. The F(1)-targeting H(+)-ATP synthase inhibitors markedly inhibited the proliferation of HUVECs, but intracellular ATP levels in HUVECs treated with these inhibitors were only slightly affected, as shown by comparison with the control cells. Interestingly, piceatannol inhibited only partially the activation of Syk (a nonreceptor tyrosine kinase), which has been shown to play a role in a number of endothelial cell functions, including cell growth and migration. These findings suggest that H(+)-ATP synthase-like molecules on the surface of HUVECs play an important role not only in extracellular ATP synthesis but also in the proliferation of HUVECs. The present results demonstrate that the use of small molecular H(+)-ATP synthase inhibitors targeting the F(1) catalytic domain may lead to significant advances in potential antiangiogenic cancer therapies.
Mol Cancer Res 2003 Nov
PMID:Possible role of cell surface H+ -ATP synthase in the extracellular ATP synthesis and proliferation of human umbilical vein endothelial cells. 1463 65


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