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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 6 patients with breast cancer - of whom specimens of the primary tumor as well as one of its metastases were available for examination - we demonstrated intratumoral and intertumoral heterogeneity in expression of activity of the glycolytic enzymes hexokinase, phosphofructokinase, aldolase, enolase and pyruvate kinase. Heterogeneity also existed in isozyme composition of pyruvate kinase. The transition of the tumors towards normal surrounding breast tissue showed either a sharp drop in activity, or a gradual decrease in activity, corresponding to pushing margins or infiltrative growth of the tumor as was demonstrated by histologic examination of these specimens. Likewise, the shift towards expression of K isozyme of pyruvate kinase in breast cancer compared to normal breast tissue could be demonstrated.
Tumour Biol 1988
PMID:Heterogeneity of glycolytic enzyme activity and isozyme composition of pyruvate kinase in breast cancer. 297 Dec 67

The activities of hexokinase, phosphofructokinase, aldolase, enolase and pyruvate kinase were studied in breast cancer metastases occurring at various sites and compared with the enzyme activities in a series of primary breast cancers. The activities of all enzymes studied were significantly higher in the metastases compared to the primary tumors (p less than or equal to 0.05). However, no changes in the isoenzyme patterns of enolase and pyruvate kinase were observed when the metastases were compared with primary breast cancers. Differences in location of the metastases did not lead to differences in enzyme activities. Our data suggest an association of an increasing rate of glycolysis with tumor progression.
Tumour Biol 1988
PMID:Glycolytic enzyme activities in breast cancer metastases. 297 47

In rapidly growing, highly glycolytic hepatoma cells as much as 65% of the total cell hexokinase is bound to the outer mitochondrial membrane [Parry, D.M., & Pedersen, P.L. (1983) J. Biol. Chem. 258, 10904-10912]. In this paper, we describe the purification to apparent homogeneity of a mitochondrial pore-forming protein from the highly glycolytic AS-30D rat hepatoma cell line. The purified protein shows a single 35 000-dalton band in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, an amino acid composition slightly more hydrophobic than that of the rat liver pore protein (also known as VDAC or mitochondrial porin), and a channel-forming activity of 136 channels min-1 (microgram of protein)-1. In addition to displaying the properties characteristic of VDAC (single-channel conductance, voltage dependence, and preference for anions), we observe that the AS-30D VDAC protein is one of only three mitochondrial proteins that bind [14C]dicyclohexylcarbodiimide (DCCD) at relatively low dosages (2 nmol of DCCD/mg of mitochondrial protein). Significantly, treatment of intact mitochondria isolated from either rat liver or the AS-30D hepatoma with DCCD results in an almost complete inhibition of their ability to binding hexokinase. Fifty percent inhibition of binding occurs at less than 2 nmol of DCCD/mg of mitochondrial protein. In contrast to DCCD, water-soluble carbodiimides are without effect on hexokinase binding. These results suggest that the pore-forming protein of tumor mitochondria forms at least part of the hexokinase receptor complex. In addition, they indicate that a carboxyl residue located within a hydrophobic region of the receptor complex may play a critical role in hexokinase binding.
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PMID:Hexokinase receptor complex in hepatoma mitochondria: evidence from N,N'-dicyclohexylcarbodiimide-labeling studies for the involvement of the pore-forming protein VDAC. 300 16

The differential tissue-specific regulation of glucokinase activity in liver and pancreatic islet cells was investigated in the insulinoma-bearing rat. A transplantable insulinoma caused hyperinsulinemia and hypoglycemia in the host by 2-3 months after implantation. Suppression of the pancreatic B-cells by the high insulin and/or low glucose manifested itself by a decrease of insulin in islet tissue. Removal of the tumor initiated transient insulin deficiency and hyperglycemia with extremes of these changes at 24 h after tumor resection. These conditions markedly affected glucose phosphorylation in the islet cells: glucokinase activity was reduced 71% in islet samples from insulinoma-bearing rats, and the enzyme fully recovered within 24 h after tumor resection. Hexokinase activity, by contrast, was not affected by these manipulations. To evaluate the relative contributions of hypoglycemia and hyperinsulinemia in islet glucokinase adaptation, glucose was intravenously infused to insulinoma-bearing rats; glycemia in excess of 150 mg/100 ml combined with excessive hyperinsulinemia resulted in a partial recovery of islet glucokinase activity, first apparent after 9 h of glucose infusion and with doubling of the activity after 24 h after glucose loading. In contrast, liver glucokinase was increased nearly 4-fold at the time of extreme hypoglycemia and hyperinsulinemia and rapidly fell to control rates following tumor removal. Intravenous infusion of glucose for 24 h into the tumor-bearing rat (i.e. hyperglycemia combined with excessive plasma insulin) had no influence on liver glucokinase activity. Liver hexokinase was not influenced by any of these experimental manipulations. The data indicate that the activities of pancreatic islet and liver glucokinase are regulated in a differential manner. Insulin is apparently the primary determinant of liver glucokinase and glucose seems to control islet glucokinase. Biochemical mechanisms for differential organ-specific regulation of glucokinase activity seem to have evolved such that this enzyme may play a dual role in glucose homeostasis, namely to serve as insulin-dependent glucose sensor in the B-cells and as insulin-sensitive determinant of hepatic glucose use.
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PMID:Differential regulation of glucokinase activity in pancreatic islets and liver of the rat. 301 39

Caloric restriction reduces the incidence and progression of a broad spectrum of neoplastic diseases, yet little is known about the biochemical and molecular mechanisms involved. Profiles of enzyme activities of importance in cellular energy utilization were examined in 7,12-dimethylbenz[a]anthracene-induced (DMBA) mammary adenocarcinomas from rats fed ad libitum or calorically restricted diets. The diets provided equal nutrients except for fewer carbohydrate-derived calories; graded caloric restriction was 10, 20, 30 and 40%. The specific activities of hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenase, malic enzyme and fructose-1,6-bisphosphatase were all elevated to varying degrees in both large palpable and small, non-palpable tumors from calorically restricted hosts compared to activities in tumors from ad libitum-fed rats. Phosphofructokinase activity was increased in palpable tumors from calorically restricted hosts but markedly reduced in non-palpable tumors. These results suggest adaptive or compensatory alterations in tumor enzyme profiles in response to the altered nutritional state of the host.
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PMID:Biochemical alterations in 7,12-dimethylbenz[a]anthracene-induced mammary tumors from rats subjected to caloric restriction. 303 94

Acceleration of glycolysis is, in general, a characteristic of neoplasia. Previous studies have shown that this increase in glycolysis is achieved by quantitative increases in the activities of the key regulatory enzymes, hexokinase, phosphofructokinase (PFK) and/or pyruvate kinase, which are often accompanied by isozymic alterations that facilitate glycolysis. In this study, we investigated the alterations in the activity, isozymic profile, and kinetic-regulatory properties of PFK from the medullary thyroid carcinomas of the rat, which represent a model for the neuroectodermally derived tumors in humans. Contrary to the expected, we found that undifferentiated tumors showed a decrease in the enzyme activity as compared to the highly differentiated tumors. This decrease in PFK activity was accompanied by an increase in the expression of the liver-type isozyme of PFK. The enzymes from the 2 tumor types showed no significant differences in their affinity and cooperativity toward the substrates, fructose 6-phosphate and adenosine triphosphate (ATP). However, the tumor PFKs showed major differences with respect to their behavior toward the allosteric regulators of the enzymes, ATP, citrate, and fructose 2,6-diphosphate; the latter is a recently discovered activator of the enzyme. The enzyme from the undifferentiated tumor was less sensitive to citrate inhibition, which was more readily reversed by cyclic adenosine 3':5'-monophosphate. In addition, it was less sensitive to ATP inhibition at low fructose 6-phosphate concentrations. More importantly, the enzyme from the undifferentiated tumors was more sensitive to the activation by fructose 2,6-diphosphate especially when inhibited by citrate and ATP. The altered regulatory properties of the enzyme from the undifferentiated tumors most probably reflect its altered isozymic composition, i.e., increase in the liver-type isozyme. The preferential expression of the liver-type isozyme by undifferentiated and rapidly replicating cancer cells may be explained in terms of the unique regulatory properties of this isozyme. Although the concentrations of fructose 2,6-diphosphate were comparable in these 2 tumor types, the higher sensitivity of the liver-type PFK to activation by this compound may permit accelerated glycolytic flux observed in undifferentiated tumors, despite a decrease in total PFK activity.
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PMID:Isozymic composition and regulatory properties of phosphofructokinase from well-differentiated and anaplastic medullary thyroid carcinomas of the rat. 315 92

The active ingredient in the tumor-promoting croton oil, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), was shown to increase the activity of mouse skin epidermal glucose-6-phosphate dehydrogenase (+84%), hexokinase (+100%), phosphofructokinase (+158%), and pyruvate kinase (+101%). This increase in activity of these key enzymes of glucose metabolism occurred 2-8 h after TPA application and was due to a net increase in the enzyme content. This increase in the activity of the glycolytic enzymes, as well as the reported TPA-induced increase in the synthesis of RNA and DNA and cell proliferation, suggest that activation of the glycolytic pathway may be involved in the carcinogenic effects of tumor promoters.
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PMID:Enhancement in the activities of mouse epidermal glucose-6-phosphate dehydrogenase, hexokinase, phosphofructokinase, and pyruvate kinase by 12-O-tetradecanoyl-phorbol-13-acetate. 315 44

Previous studies from this laboratory have shown that mitochondrial bound hexokinase is markedly elevated in highly glycolytic hepatoma cells (Parry, D. M., and Pedersen, P.L. (1983) J. Biol. Chem. 258, 10904-10912). A pore-forming protein, porin, within the outer membrane appears to comprise at least part of the receptor site (Nakashima, R.A., Mangan, P.S., Colombini, M., and Pedersen, P.L. (1986). Biochemistry 25, 1015-1021). In studies reported here experiments were carried out to assess the functional significance of mitochondrial bound tumor hexokinase. Two approaches were used to determine whether the bound enzyme has preferred access to mitochondrially generated ATP relative to cytosolic ATP. The first approach compared the time course of glucose 6-phosphate formation by AS-30D hepatoma mitochondria under conditions where ATP was regenerated endogenously via oxidative phosphorylation or exogenously by added pyruvate kinase and phosphoenolpyruvate. The second approach involved the measurement of the specific radioactivity of glucose 6-phosphate formed following the addition of [gamma-32P]ATP to either phosphorylating or nonphosphorylating AS-30D mitochondria. Both approaches provided results which show that the source of ATP for bound hexokinase is derived preferentially from the ATP synthase residing within the inner mitochondrial membrane compartment rather than from the medium (i.e. from the cytosolic compartment). These results provide the first direct demonstration that the exceptionally high level of hexokinase bound to mitochondria of highly glycolytic tumor cells has preferred access to mitochondrially generated ATP, a finding that may have rather profound metabolic significance for such tumors.
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PMID:Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP. 318 54

Lonidamine (LND) has been shown to inhibit tumor aerobic glycolysis. Its effect was evaluated on several human astrocytomas at different degrees of malignancy; a correlation was found between LDN effect on lactate production and tumor malignancy: in grade I and II astrocytomas LND stimulates lactate production, while in grade III, IV and glioblastoma multiforme lactate production is inhibited. In an attempt to explain this different behaviour, hexokinase content and compartmentation was evaluated in astrocytomas from fresh operatory specimens and from cultured cells as well, observing a significative correlation between malignancy, hexokinase activity, percent of mitochondrially-bound hexokinase and LND effect. The results justify from a biochemical point of view the role of LND as a 'non-conventional' agent in multimodality combined treatment for malignant gliomas.
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PMID:Effect of lonidamine on human malignant gliomas: biochemical studies. 322 40

Recent studies from this laboratory have demonstrated that a form of hexokinase characteristic of rapidly growing, highly glycolytic tumor cells is bound to an outer mitochondrial membrane receptor complex containing a Mr 35,000 pore protein (D. M. Parry and P. L. Pedersen, J. Biol. Chem., 258: 10904-10912, 1983; R. A. Nakashima, et al., Biochemistry, 25: 1015-1021, 1986). In new studies reported here the specificity of this receptor complex for binding hexokinase is defined, and a purification scheme is described which leads to a homogeneous and bindable form of the tumor hexokinase. In the AS-30D hepatoma, hexokinase activity is elevated more than 100-fold relative to liver tissue. The relative increase in hexokinase activity is 8 times greater than that of any other glycolytic enzyme. Hexokinase is the only glycolytic enzyme of AS-30D cells to exhibit a mitochondrial/cytoplasmic specific activity ratio greater than 1, showing a 3.5-fold elevation in the mitochondrial fraction. Purification of hexokinase is accomplished by preferential solubilization of the mitochondrial bound enzyme with glucose-6-phosphate, followed by high-performance liquid chromatography on gel permeation and anion exchange columns. The final fraction has a specific activity of 144 units per mg of protein, with a Km for glucose of 0.13 mM and for ATP of 1.4 mM. The purified tumor enzyme migrates as a single species upon sodium dodecyl sulfate: polyacrylamide gel electrophoresis with an apparent molecular weight of 98,000. Significantly, the purified tumor enzyme retains its activity for mitochondrial binding. Additional results derived from chromatographic, polyclonal antibody, and amino acid analysis studies indicate that the predominant rat hepatoma hexokinase species is related most closely to isozymic form(s) of the enzyme commonly referred to as type II, and least related to the liver type IV isozyme (glucokinase).
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PMID:Purification and characterization of a bindable form of mitochondrial bound hexokinase from the highly glycolytic AS-30D rat hepatoma cell line. 333 84


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