Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.34 (lipoprotein lipase)
 7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rates of lipogenesis and lipoprotein lipase (LPL) activity were measured in liver, adipose tissue, heart, and tumor at several stages during 10 days of palpable growth of a transplantable Leydig cell tumor in rats. This model showed the same characteristics as human cancer cachexia, including anorexia, weight loss, and muscle wasting. Comparison with pair-fed controls showed that the rate of loss of body fat was greater than could be explained by anorexia alone. The rate of lipogenesis tended to decrease during the later stages of tumor growth, particularly in the liver, where there was a statistically significant reduction on Days 5 and 10. This may be largely attributable to decreased availability of substrates caused by decreasing food intake and increasing glucose uptake by the tumor. There was a significant decrease in plasma glucose concentration by Day 10. In contrast, LPL activity in adipose tissue was depressed from the earliest stage of tumor growth, and this is likely to be a major cause of lipid depletion in cancer. There was no difference in adipose tissue LPL activity between the fed and postabsorptive states in the tumor-bearing rats, indicating that the normal response to nutrient intake was impaired. Thus, treatment of cancer cachexia should concentrate on normalizing the metabolic response to nutrient ingestion.
Nutr Cancer 1993
PMID:Lipid metabolism in cachectic tumor-bearing rats at different stages of tumor growth. 844 17

Nontransformed 3T3 T mesenchymal/proadipocyte stem cells can be readily induced to differentiate, yet previous work has shown that 3T3 T cells that are spontaneously or virally transformed not only lose their normal growth control mechanisms but also lose the ability to differentiate. Loss of growth control can be due to autocrine mechanisms in some transformed cells, but the mechanisms involved in disrupting differentiation control are poorly understood. Our goal is to further define the growth and differentiation defects that arise in neoplastically transformed cells and the mechanisms underlying those defects. For example, exogenous transforming growth factor beta and tumor necrosis factor, both of which are secreted aberrantly by some tumor cells, are known inhibitors of different steps of the normal 3T3 T adipocyte differentiation process, suggesting a potential role as autocrine factors in disrupting differentiation of transformed 3T3 T cells. In the current study we transformed 3T3 T cells in vitro with chemical or UV irradiation treatment in order to determine if the acquisition of the transformed phenotype after these treatments is also associated with loss of differentiation control as it is with spontaneously or virally transformed cells. Four chemically and two UV-treated 3T3 T cell lines were isolated from type III foci and all have been found to be tumorigenic in syngeneic animals and to have lost the ability to differentiate. Relative to the parental cell line the differentiation abilities of the transformed clones ranged from 0 to less than 5%. In this regard, we also analyzed the normal and aberrant expression of three growth factors and differentiation inhibitors in transformed cells. Both transforming growth factor alpha and beta were found to be expressed in non-transformed 3T3 T cells as determined by Northern blot analyses. In addition, both were found to be down-regulated during differentiation of 3T3 T cells. Transformed/differentiation-defective 3T3 T cells expressed varied levels of transforming growth factor alpha and beta. Three of the new transformed clones expressed particularly high levels of transforming growth factor alpha. Very low levels of tumor necrosis factor expression were found in the normal cells and the transformed cells appeared to express tumor necrosis factor at similar levels. In contrast, none of the transformed cells expressed any of the differentiation-specific genes tested (lipoprotein lipase, glycerol-3-phosphate dehydrogenase, etc.). Even a transformed clone which could undergo growth arrest but not morphological differentiation expressed no differentiation-specific genes. Together, these data suggest that neoplastic transformation in general disrupts differentiation control.(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Res 1993 Apr 15
PMID:Loss of differentiation control in transformed 3T3 T proadipocytes. 846 95

Cachexia is a common problem in the clinical management of cancer patients, particularly those with solid tumors. Cachexia is most obviously manifested as weight loss with massive depletion of both adipose tissue and muscle mass, and death is probably due to loss of lean body tissue. Not only is the survival time shorter in patients with cachexia, but the frequency of response to chemotherapy is also significantly reduced. Although anorexia frequently accompanies cachexia, attempts to halt or reverse cachexia by nutritional repletion have not been successful. This suggests that cachexia is due to metabolic abnormalities produced by the tumor in addition to the underlying anorexia. In some patients weight loss is associated with an increased relative energy expenditure possibly through an elevated adrenergic state. Several factors have been postulated as mediators of cancer cachexia and can be divided into two groups. (i) Materials with hormone-like characteristics which result in direct catabolism of host tissues. (ii) Cytokines which cause alterations in host metabolism indirectly. Included in group (i) are the conventional catabolic hormones and a lipid mobilizing factor (LMF) produced by tumors, which causes direct breakdown of adipose tissue. Included in group (ii) are tumor necrosis factor-alpha, interleukin-6, interferon-gamma and leukaemia inhibitory factor. The materials appear to influence adipose tissue indirectly through an inhibition of lipoprotein lipase. Reversal of cachexia has been achieved by two groups of agents. (i) Those stimulating food intake, e.g. megestrol acetate. (ii) Those directly inhibiting the LMF, e.g. eicosapentaenoic acid. While agents in group (i) can cause tumor growth stimulation, those in group (ii) act as tumor growth inhibitors. This latter results suggests that the products of catabolism of host tissues may be important for tumor growth and provides a new avenue for chemotherapeutic intervention.
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PMID:Cancer cachexia. 849 Jan 91

Enhancement of in vitro cytotoxic activity of tumor necrosis factor-alpha (TNF-alpha) was observed in combination with lysosome labilizers, particularly with urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) and lipoprotein lipase (LPL). The concentration of TNF-alpha resulting in 50% cytotoxicity to L929 cells was only 20-30% of the value for TNF-alpha alone, when used in combination with a nontoxic dose of u-PA, t-PA or LPL. Furthermore, combined intravenous (i.v.) administration of TNF-alpha (3.5 x 10(5) U/mouse) and u-PA (300 IU/mouse) markedly increased the in vivo antitumor activity of TNF-alpha to Meth A tumors transplanted into BALB/c mice; the tumor weight in co-administered mice was about 40% of that in mice given TNF-alpha alone on day 6. The combination therapy of TNF-alpha (7.0 x 10(4) U/mouse, i.v.) and u-PA (300 IU/mouse, i.v.) was also effective for L929 tumors in Crj:CD-1(1CR)-nu nude mice compared with the conventional therapy with TNF-alpha alone. These results suggest that the combination of TNF-alpha and lysosome labilizers is a promising antitumor therapeutic regimen with clinical potential.
Jpn J Cancer Res 1993 Apr
PMID:Lysosome labilizers potentiate the antitumor effects of tumor necrosis factor-alpha. 851 12

The activity of lipoprotein lipase (LPL), a key regulatory enzyme for triglyceride (TG) clearance from plasma, is reported to decrease as the tumor burden increases in tumor-bearing animals and patients with lung cancer; therefore, it is believed to play a key role in inducing cancer cachexia. We attempted to reverse cancer cachexia by stimulating LPL activity with an antihypertriglyceridemic drug, bezafibrate. Bezafibrate, which reduces circulating TG levels by stimulating tissue LPL activity, has been used clinically in patients with hypertriglyceridemia. Bezafibrate was administered subcutaneously to 24 rats at a dose of 30 mg/kg per day from the 8th day after tumor inoculation with methylcholanthrene-induced sarcoma until they were killed on either the 25th or 33rd day, at the precachectic and cachectic stages, respectively. The animals were divided into the following three groups: treated tumor-bearing rats (treated TBR group), untreated TBRs (untreated TBR group), and a control (CTR) group. LPL activities in both the adipose tissue and cardiac muscle were measured by the method of Nilsson-Ehle and Schotz. Both TG and nonesterified fatty acid (NEFA) became elevated as the size of the tumor increased in the TBRs; however, this increment was quantitatively less in the treated TBR group than in the untreated TBR group. The administration of bezafibrate resulted in preservation of the epididymal fat pad mass at the cachectic stage. A significant decrease in LPL activity in the epididymal fat was observed in the untreated TBR group at the cachectic stage, but this was prevented in the treated TBR group, the values being 2.97 +/- 1.37 U/whole tissue in the untreated TBR group, 4.03 +/- 1.11 in the treated TBR group, and 10.15 +/- 6.61 in the CTR group. Thus, tumor growth in the treated TBR group at the cachectic stage was significantly suppressed compared with that of the untreated TBR group. These results suggest that the decreased LPL activity that occurs in the tumor-bearing state can be stimulated by the antihyperlipidemic drug bezafibrate, which may modulate some of the tumor-bearing state can be stimulated by the antihyperlipidemic drug bezafibrate, which may modulate some of the tumor-induced metabolic alterations leading to cancer cachexia.
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PMID:Stimulation of decreased lipoprotein lipase activity in the tumor-bearing state by the antihyperlipidemic drug bezafibrate. 891 77

The inoculation of the Yoshida AH-130 ascites hepatoma to rats resulted in an important loss of adipose tissue associated with a decrease in lipoprotein lipase (LPL) activity. Tumour burden also resulted in an important hyperlipidemia which affected both triglyceride and free fatty acids. Administration of phentolamine (an alpha-adrenergic antagonist) to tumour-bearing rats did not influence LPL activity, but it reversed the increase in plasma triglycerides associated with tumour burden. It is suggested that the hypertriglyceridemia associated with tumour growth may be, in part, a consequence of the effect of catecholamines on hepatic triglyceride secretion, via alpha-adrenergic receptors.
Cancer Lett 1996 Dec 20
PMID:alpha-Adrenergic receptors may contribute to the hypertriglyceridemia associated with tumour growth. 901 4

The implantation of the Lewis lung carcinoma (a fast-growing mouse tumour that induces cachexia) to both wild-type and gene-deficient mice for the tumour necrosis factor (TNF) receptor type I protein (Tnfr1(0)/Tnfr1(0)), resulted in a considerable loss of carcass (26%) and white (77%) and brown adipose (37%) tissue weights in the wild-type mice, while it induced much less marked effects in the gene-deficient mice. Tumour burden also inflicted an important decrease in total lipoprotein lipase (LPL) activity in epididymal white adipose tissue (50%) in the wild-type mice while no changes were observed in the knockout mice. In addition, all tumour-bearing animals were clearly hypertriglyceridaemic (80% increase in circulating triacylglycerols in wild-type and 36% in knockout mice). It is concluded that although TNF seems to be to some extent responsible for adipose waste, LPL changes and hyperlipaemia (via receptor I), the role of other cytokines (alone or in combination with TNF) in promoting changes in lipid metabolism during cancer cachexia cannot be discarded.
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PMID:Lipid metabolism in tumour-bearing mice: studies with knockout mice for tumour necrosis factor receptor 1 protein. 932 50

Loss of heterozygosity at chromosome 8p21-22 is common in human prostate cancer, suggesting the presence of one or more tumor suppressor genes at this locus. A homeobox gene that is expressed specifically in adult human prostate, NKX3.1, the expression of which is regulated by androgen, maps to chromosome 8p21. Fine structure in situ mapping showed that NKX3.1 is proximal to MSR32 (macrophage scavenger receptor type II) and LPL (human lipoprotein lipase) and very close to NEFL (human neurofilament light chain) on 8p21. Single-strand conformational polymorphism analysis of 48 radical prostatectomy cancer specimens and 3 metastases for the entire coding region of NKX3.1 showed no tumor-specific sequence alterations in 50 specimens and total absence of the gene in 1 specimen known to have a biallelic deletion of 8p21. NKX3.1 was found to have a polymorphism at nucleotide 154 in codon 52 that resulted in a CGC-->TGC sequence change and an Arg-->Cys amino acid alteration (R52C). This polymorphism was present in 20% of DNA samples. If NKX3.1 is a target of the 8p21 LOH, it is not via disruption of the coding region of the gene.
Cancer Res 1997 Oct 15
PMID:Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers. 937 51

HS influences fundamental cellular properties and biochemical processes at the cell surface. In addition to the issues already discussed, it has a profound effect on cell adhesion and migration through its interaction with many extracellular matrix proteins, most notably fibronectin and thrombospondin; it is closely linked to lipid metabolism through its capacity to bind low-density lipoprotein and lipoprotein lipase; and aberrations in HS structure and degradation are linked to human malignancy and Alzheimer's disease [26,27]. The subtle variations in HS structure enable it to distinguish between families of related proteins such as the FGFs, the chemokines [28] and the TGF beta s [29]. The multifunctional nature of HS is the result of its structural diversity and strategic positioning in the pericellular domain. The biosynthesis of HS, in common with other complex carbohydrates, is not directed by any known template yet the system is clearly subject to quite precise control so that in general, the HS family has a common domain organization that is finely tuned at the cellular level to produce HS species of variable length, fine structure and biological properties. A major challenge for future research will be to unravel the regulatory mechanisms that determine the molecular structure of HS. It remains unclear whether these mechanisms are entirely intrinsic in nature or subject to substantial modulation by the cellular microenvironment.
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PMID:Structure-activity relationship of heparan sulphate. 944 76

Cathepsin B (CTSB) is overexpressed in tumors of the lung, prostate, colon, breast, and stomach. However, evidence of primary genomic alterations in the CTSB gene during tumor initiation or progression has been lacking. We have found a novel amplicon at 8p22-23 that results in CTSB overexpression in esophageal adenocarcinoma. Amplified genomic NotI-HinfI fragments were identified by two-dimensional DNA electrophoresis. Two amplified fragments (D4 and D5) were cloned and yielded unique sequences. Using bacterial artificial chromosome clones containing either D4 or D5, fluorescent in situ hybridization defined a single region of amplification involving chromosome bands 8p22-23. We investigated the candidate cancer-related gene CTSB, and potential coamplified genes from this region including farnesyl-diphosphate farnesyltransferase (FDFT1), arylamine N-acetyltransferase (NAT-1), lipoprotein lipase (LPL), and an uncharacterized expressed sequence tag (D8S503). Southern blot analysis of 66 esophageal adenocarcinomas demonstrated only CTSB and FDFT1 were consistently amplified in eight (12.1%) of the tumors. Neither NAT-1 nor LPL were amplified. Northern blot analysis showed overexpression of CTSB and FDFT1 mRNA in all six of the amplified esophageal adenocarcinomas analyzed. CTSB mRNA overexpression also was present in two of six nonamplified tumors analyzed. However, FDFT1 mRNA overexpression without amplification was not observed. Western blot analysis confirmed CTSB protein overexpression in tumor specimens with CTSB mRNA overexpression compared with either normal controls or tumors without mRNA overexpression. Abundant extracellular expression of CTSB protein was found in 29 of 40 (72. 5%) of esophageal adenocarcinoma specimens by using immunohistochemical analysis. The finding of an amplicon at 8p22-23 resulting in CTSB gene amplification and overexpression supports an important role for CTSB in esophageal adenocarcinoma and possibly in other tumors.
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PMID:A novel amplicon at 8p22-23 results in overexpression of cathepsin B in esophageal adenocarcinoma. 977 May


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