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PubMed1980

Radiosensitive, thymic hormone-sensitive peripheral blood suppressor cell activity in cancer patients.

Suppressor cell activity which was radiosensitive in most subjects and thymic hormone sensitive in some was identified in patients with cancer, and compared to simultaneously studied normal controls. Suppressor cell activity was measured in cocultures of normal lymphocytes with patient lymphocytes added in microwells using the blastogenic response to phytohemagglutinin and concanavalin A as the measure of activity. Thirty-five patients (lung cancer, 21; leukemia in remission, seven; and various solid tumors, seven) and an equal number of controls were studied. Suppressor cell activity was identified in 71% of the patients. In approximately 75% of these, the suppressor cell activity was radiosensitive (4000 to 6000 rads). For the phytohemagglutinin response, suppressor cell activity was thymic hormone sensitive in approximately 40% (Thymosin Fraction 5 or thymic humoral factor), and for the concanavalin A response, it was thymic hormone sensitive in about 25% of the cases. There was a significant correlation between the presence of immunodeficiency (defined as a phytohemagglutinin response < 35,000 or a concanavalin A response < 12,000 cpm) and the presence of the suppressor cell activity. The suppressor cell activity was heterogenous relative to its radiosensitivity and thymic hormone sensitivity. Suppressor cell activity was observed in all the patient categories. These results indicate that certain available therapeutic manipulations may have significant effects on suppressor cell activity and should be an important subject for further investigation.

Antineoplastic Agents↗
PubMed1994

The multifunctional role of hormone-sensitive lipase in lipid metabolism.

Hormone sensitive lipase (HSL) is an enzyme of relatively broad specificity, having the ability to hydrolyze tri-, di- and mono-acylglycerols as well as cholesterol esters and small water-soluble substrates. This broad specificity allows HSL to perform a variety of functions in several tissues. A key feature of HSL is its ability to be activated via phosphorylation by cyclic AMP-dependent protein kinase. In addition it is phosphorylated at a second site by several kinases, notably AMP-activated protein kinase. Phosphorylation of this site apparently plays a role in rendering the enzyme hormone-insensitive, in that prior phosphorylation at site 2 prevents phosphorylation and activation at site 1 by cyclic AMP-dependent protein kinase. Investigation of the protein phosphatases responsible for dephosphorylation of these sites has indicated that phosphatase 2A plays a predominant role but also that protein phosphatase 2C is a significant phosphatase targeted against both phosphorylation sites. Evidence indicates that HSL has at least three functional domains which contain (a) the phosphorylation sites which control activity, (b) the active site responsible for the catalytic activity and (c) a lipid binding site responsible for anchoring the lipase at the water-lipid interface. Using limited proteolytic studies we have found that it is possible to cleave HSL into several fragments including a stable domain of M(r) approximately 17.6 kDa which contains the active site serine residue. Digestion under similar conditions also generates a stable domain of M(r) approximately 11.5 kDa containing both phosphorylation sites. Furthermore, under appropriate conditions it is possible to digest HSL and retain activity against water-soluble substrates but with the concomitant loss of activity against triacylglycerol, implying that a lipid binding domain is lost during this procedure. HSL is responsible for the neutral cholesterol esterase activity in macrophages and it may play a role in the accumulation of cholesterol esters which occur during the development of foam cells. HSL activity is reduced in macrophage foam cells, at least partly due to increased activity of a cytosolic HSL inhibitor protein. A finding unexplained for many years has been that, although lipolysis can be stimulated 50-100-fold in adipocytes by lipolytic hormones, HSL can apparently only be activated 2-3-fold via phosphorylation in vitro by cyclic AMP-dependent protein kinase. One possibility to explain this discrepancy is that an additional anchoring protein is missing from the in vitro system and indirect evidence is now accumulating for such a protein.

Adipose Tissue↗
PubMed1994

Regulation of hormone-sensitive lipase during fasting.

Hormone-sensitive lipase (HSL) is the rate-limiting enzyme in lipolysis. The activity of HSL is thought to be primarily regulated by phosphorylation-dephosphorylation reactions. Although FFA levels are elevated during fasting, it has been difficult to demonstrate an increase in HSL activity with fasting. The current studies were undertaken to explore directly the regulation of HSL expression in adipose tissue in the rat during fasting. Rats were fasted for periods up to 5 days and HSL activity, HSL immunoreactive protein, and HSL mRNA levels were measured both in intact epididymal adipose tissue and in isolated adipose cells. Fasting caused a progressive decline in total body weight and the weight of epididymal fat pads, whereas adipose cell size decreased approximately 50% after 2 days of fasting. Serum FFA levels approximately doubled within 1 day of fasting and remained elevated thereafter. Basal lipolysis, measured as glycerol release, did not increase until 2 days of fasting. HSL activity remained relatively unchanged until 3 days of fasting when it was increased twofold after 3-5 days of fasting. Likewise, HSL immunoreactive protein and HSL mRNA levels increased twofold after 3-5 days of fasting. Thus HSL activity appears to be regulated by pretranslational mechanisms during prolonged fasting. However, increases in FFA flux during short-term fasting appear to involve either post-translational control of HSL or the regulation of other enzymes.

Animals↗
PubMed2002

Transcriptional regulation of adipocyte hormone-sensitive lipase by glucose.

Hormone-sensitive lipase (HSL) catalyzes the rate-limiting step in the mobilization of fatty acids from adipose tissue, thus determining the supply of energy substrates in the body. HSL mRNA was positively regulated by glucose in human adipocytes. Pools of stably transfected 3T3-F442A adipocytes were generated with human adipocyte HSL promoter fragments from -2,400/+38 to -31/+38 bp linked to the luciferase gene. A glucose-responsive region was mapped within the proximal promoter (-137 bp). Electromobility shift assays showed that upstream stimulatory factor (USF)-1 and USF2 and Sp1 and Sp3 bound to a consensus E-box and two GC-boxes in the -137-bp region. Cotransfection of the -137/+38 construct with USF1 and USF2 expression vectors produced enhanced luciferase activity. Moreover, HSL mRNA levels were decreased in USF1- and USF2-deficient mice. Site-directed mutagenesis of the HSL promoter showed that the GC-boxes, although contributing to basal promoter activity, were dispensable for glucose responsiveness. Mutation of the E-box led to decreased promoter activity and suppression of the glucose response. Analogs and metabolites were used to determine the signal metabolite of the glucose response. The signal is generated downstream of glucose-6-phosphate in the glycolytic pathway before the triose phosphate step.

3T3 Cells↗
PubMed1989

Phosphorylation of bovine hormone-sensitive lipase by the AMP-activated protein kinase. A possible antilipolytic mechanism.

Hormone-sensitive lipase is phosphorylated at a single site (site 2) in vitro by the AMP-activated protein kinase, without any direct effect on the activity of the enzyme. The amino acid sequence around this site has been determined. Ca2+/calmodulin-dependent protein kinase II also phosphorylates hormone-sensitive lipase predominantly at this site, whilst cyclic-GMP-dependent protein kinase phosphorylates exclusively the regulatory site (site 1) which is also phosphorylated by cyclic-AMP-dependent protein kinase. Phosphorylation of site 2 has been found to inhibit subsequent phosphorylation and activation of hormone-sensitive lipase by the cyclic-AMP-dependent and cyclic-GMP-dependent protein kinases, indicating that site-2 phosphorylation may have an antilipolytic role in vivo.

Animals↗
PubMed1984

Hormonal regulation of hormone-sensitive lipase in intact adipocytes: identification of phosphorylated sites and effects on the phosphorylation by lipolytic hormones and insulin.

In isolated adipocytes, fast-acting lipolytic hormones and insulin have been shown previously to control lipolysis by regulating the activity of hormone-sensitive lipase, the rate-limiting enzyme, through an increase or decrease, respectively, of the extent of phosphorylation of the enzyme. Here, we demonstrate that exposure to lipolytic hormones (corticotropin, noradrenaline) led to phosphorylation at two sites on the Mr 84,000 lipase subunit. One, designated "basal site," was phosphorylated also in the absence of any hormonal stimulation, its phosphorylation apparently not being influenced by hormones. The second, designated "regulatory site," was identical to that phosphorylated by cyclic AMP-dependent protein kinase on the isolated lipase. The regulatory site was not appreciably phosphorylated in the absence of hormones, but exposure of the cells to noradrenaline increased its phosphorylation extent to that of the basal site. Insulin or the beta-adrenergic antagonist propranolol decreased the extent of phosphorylation of the regulatory site to the low level before stimulation, apparently without effect on the basal site. Phosphoserine was the only phosphorylated amino acid residue at both sites. Limited proteolytic digestion indicated that the two sites were separated by less than about 170 amino acid residues. Thus, control of adipose tissue lipolysis by fast-acting lipolytic hormones and by insulin is exerted through the regulation of the phosphorylation state of a single phosphoserine residue in the hormone-sensitive lipase.

Adipose Tissue↗
PubMed1984

Direct evidence for protein phosphatase-catalyzed dephosphorylation/deactivation of hormone-sensitive lipase from adipose tissue.

Incubation of purified hormone-sensitive lipase, 32P-phosphorylated with the catalytic subunit of cyclic AMP-dependent protein kinase and [gamma-32P]ATP-Mg2+, with partially purified protein phosphatase from the same tissue caused a rapid decrease of the 32P content of the enzyme protein. Deactivation of the lipase towards emulsified trioleoylglycerol was temporally related to the dephosphorylation with approx. 80% decrease of both phosphorylation and activity within 30 min. Addition of ATP-Mg and cyclic AMP-dependent protein kinase to the dephosphorylated lipase was shown to rephosphorylate and reactivate the enzyme. These findings are the first direct demonstration of reversible protein phosphatase-catalyzed dephosphorylation/deactivation of hormone-sensitive lipase.

Adenosine Triphosphate↗
PubMed2001

Insulin mediated inhibition of hormone sensitive lipase activity in vivo in relation to endogenous catecholamines in healthy subjects.

The regulation of hormone-sensitive lipase activity in vivo has not been studied in detail before. We have performed noninvasive in vivo tests to measure hormone-sensitive lipase activity under high plasma levels of endogenous insulin and catecholamines. For this purpose, two mental stress tests were carried out at random in 13 healthy volunteers. The subjects ingested 200 ml of a placebo solution or 20% glucose, followed by 1 h of rest, 20 min of mental stress, and 40 min of rest. Twenty minutes after the ingestion of glucose, insulin levels increased from 6.8 +/- 1.6 to a maximum of 30.5 +/- 4.8 mU/liter (P < 0.01), whereas the increase in insulin was significantly less after placebo (from 5.7 +/- 0.9 to 9.5 +/- 1.5 mU/liter; P < 0.01). The increase in heart rate, as an estimate of the amount of stress, was similar in both tests (12% increase). During stress, plasma norepinephrine and epinephrine concentrations increased by 24% and 44%, respectively, after glucose and by 4% and 21%, respectively, after placebo (n = 6). Fasting plasma FFA were similar in both tests (placebo, 0.35 +/- 0.07 mM; glucose, 0.46 +/- 0.08 mM). Forty minutes after ingestion of placebo, plasma FFA concentrations decreased to 0.27 +/- 0.07 mM, compared with a stronger suppression to 0.11 +/- 0.02 mM after ingestion of glucose (P < 0.01). By 10 min after mental stress, plasma FFA concentrations increased by 53% after placebo (P < 0.01), in contrast to unchanged FFA concentrations after ingestion of glucose. Taken together, these results suggest that the suppression of hormone-sensitive lipase by endogenous insulin in healthy, insulin-sensitive subjects is stronger than the stimulation by endogenous catecholamines.

Adult↗
PubMed1993

[Biochemical paths for regulating hormone-sensitive cells].

The main causes of alterations in cell sensitivity to steroid hormones were studied during malignant growth and upon ageing. In many cases studied the decreased sensitivity of cells to steroids was reversible and unrelated to changes in the receptor system of the cell. Based on the data obtained, a hypothesis was proposed concerning the multifunctional regulation of cell sensitivity to hormones. Within the framework of this hypothesis the sensitivity of cells to hormones is regulated by both changes in the receptor system responsible for hormonal signal transmission and by changes in the activity of hormone-dependent intracellular enzymatic systems. The role of target cell microenvironment in the formation of the ultimate cell response to hormonal stimuli is discussed.

Aging↗
PubMed1995

Hormonal regulation of adenylate cyclase activity in circulating lymphocytes and its interrelationship with hormone sensitivity of tumor tissue in colorectal cancer patients.

The purpose of this study was to investigate the peculiarities of hormonal regulation of adenylate cyclase (AC) of blood lymphocytes in colorectal cancer patients and to compare these peculiarities with hormone sensitivity of AC of colorectal tumors and normal colonic mucosa. Basal and stimulated lymphocyte AC activity was studied in 51 healthy persons and 52 cancer patients (14 with colon cancer, 21 with rectal cancer and 17 with stomach cancer) aged 20-75 years. In 31 of 35 patients with colorectal cancer the AC activity was studied simultaneously in lymphocytes, tumor tissue and normal colonic mucosa. To evaluate basal and stimulated AC activity the measurement of c-AMP (Amersham kits) formed in the presence of ATP regenerating system was used. Basal and by VIP, pentagastrin and sodium fluoride stimulated AC activity in lymphocytes of gastrointestinal cancer patients was lower than in lymphocytes of healthy subjects of similar age. Stage dependence of the parameters under study was not found. There was a tendency for higher basal and stimulated lymphocyte AC activity in colon cancer patients as compared to stomach and rectal cancer patients. In colorectal cancer patients the peculiarities of lymphocyte AC reactions to stimulation were closer to those in tumor tissue but not to those in normal colonic mucosa. The reaction of lymphocyte AC to VIP and glucagon coincided more frequently with tumor AC reactions to the same hormones in case of hormone nonsensitive tumors. Thus, basal and stimulated lymphocyte AC activity in colorectal cancer patients was modified to some degree by tumor factors. Lymphocyte AC reactions to VIP and glucagon may be considered as indirect markers of hormone sensitivity of colonic tumors. Moreover, the probability of discovery of hormone nonsensitive tumors by this way is more reliable than hormone sensitive ones.

Adenosine Triphosphate↗
PubMed1994

Localization of hormone-sensitive lipase to rat Sertoli cells and its expression in developing and degenerating testes.

Using in situ hybridization, hormone-sensitive lipase was found to be expressed in a stage-dependent manner in Sertoli cells of rat testis. No expression was found in Leydig cells but expression in spermatids could not be excluded. These results suggest a role for hormone-sensitive lipase in the metabolism of lipid droplets in Sertoli cells, in contrast to its previously proposed function in steroid biosynthesis. The expression of testicular hormone-sensitive lipase mRNA and protein, both larger in size compared to other tissues, coincided with the onset of spermatogenesis and was dependent on scrotal localization of the testis, suggesting a temperature-dependent, pretranslational regulation of expression.

Animals↗
PubMed2000

Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology Group study.

PURPOSE: Although hormonal therapy represents standard therapy for metastatic hormone-sensitive disease, many patients receive initial chemotherapy because of the location, bulk, or aggressiveness of their disease. It is uncertain whether simultaneous hormonal therapy provides additional benefit compared with chemotherapy alone. Eastern Cooperative Oncology Group trial E3186 was initiated to explore this question. PATIENTS AND METHODS: Between January 1988 and December 1992, 231 patients with estrogen receptor (ER)-positive or ER-unknown metastatic breast cancer were randomized to receive either chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil ¿CAF) or chemohormonal therapy (CAF plus tamoxifen and Halotestin ¿fluoxymesterone; Pharmacia-Upjohn, Kalamazoo, MI ¿CAFTH) as front-line therapy for metastatic breast cancer. Patients who experienced a complete response to induction therapy either received or did not receive maintenance cyclophosphamide, methotrexate, fluorouracil, prednisone, and TH as a secondary randomization. RESULTS: The response rates (complete response and partial response) of patients who received CAF and CAFTH were similar (69.2% v 68.9%, respectively; P =.99). Time to treatment failure (TTF) was slightly longer for patients who received chemohormonal therapy compared with chemotherapy alone patients (13.4 months v 10.3 months, respectively; P =.087), and TTF was significantly longer in ER-positive compared with ER-negative patients (17.4 months v 10.3 months, respectively; P =.048). However, ER status had no effect on overall survival (30.0 months for CAF v 29.3 months for CAFTH). CONCLUSION: In patients with potentially hormone-sensitive metastatic breast cancer, chemohormonal therapy prolongs TTF for ER-positive patients without improving overall survival.

Adult↗
PubMed1989

The presence and role of hormone-sensitive lipase in heart muscle.

Hormone-sensitive lipase (HSL) catalyses the initial, rate-limiting, reaction in adipose-tissue lipolysis. Hormone-stimulated lipolytic activity has also been observed in the heart, where endogenous triacylglycerol is the major energy store. However, the identity of the intracellular lipase responsible has yet to be established. We have partially purified a neutral lipase from bovine heart muscle and compared its properties with those of HSL from bovine adipose tissue. The heart lipase has the same subunit Mr as HSL, is immunoprecipitated by antiserum raised against purified HSL and is phosphorylated by cyclic AMP-dependent protein kinase, apparently at the same site as HSL (as judged by h.p.l.c. of tryptic phosphopeptides). Phosphorylation of the heart lipase was found to result in increased enzyme activity, demonstrating the lipase's potential to respond to hormonal stimuli. The heart lipase was shown to be present in myocytes by its immunoprecipitation from homogenates of rat myocytes by anti-HSL antiserum. These findings are consistent with the conclusion that HSL is responsible for intracellular lipolysis in heart.

Adipose Tissue↗
PubMed1999

Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects.

Decreased lipolytic effect of catecholamines in adipose tissue has repeatedly been demonstrated in obesity and may be a cause of excess accumulation of body fat. However, the mechanisms behind this lipolysis defect are unclear. The role of hormone-sensitive lipase was examined using abdominal subcutaneous adipocytes from 34 obese drug-free and otherwise healthy males or females and 14 non-obese control subjects. The enzyme catalyzes the rate-limiting step of the lipolysis pathway. The maximum lipolytic capacity of fat cells was significantly decreased in obesity when measured using either a non-selective beta-adrenergic receptor agonist (isoprenaline) or a phosphodiesterase resistant cyclic AMP analogue (dibutyryl cyclic AMP). Likewise, enzyme activity, protein expression, and mRNA of hormone-sensitive lipase were significantly decreased in adipocytes of obese subjects. The findings were not influenced by age or gender. The data suggest that a decreased expression of hormone-sensitive lipase in subcutaneous fat cells, which in turn causes decreased enzyme function and impaired lipolytic capacity of adipocytes, is present in obesity. Impaired expression of the hormone-sensitive lipase gene might at least in part explain the enzyme defect.

Adipose Tissue↗
PubMed1988

A dynamic test of hormonal sensitivity of gynecologic malignancy by use of an antiestrogen, tamoxifen.

To assess the hormonal sensitivity of tumors, progestin receptor levels in the tumor were monitored before and after tamoxifen, 40 mg/day for 7 days in patients with various gynecologic malignancies. Tamoxifen induced progestin receptors in two of eight-cases of endometrial cancer, four of eight cases of cervical epidermoid cancer, and two of seven cases of cervical adenocarcinoma. Induction of progestin receptors did not occur in one case of uterine mixed müllerian tumor and there were no measured progestin receptors after tamoxifen treatment in three cases of ovarian cancer and in one case of benign ovarian tumor. Because induction of progestin receptors is the best-documented response of estrogen target cells to estrogenic stimuli, this induction of progestin receptor with tamoxifen may be considered to indicate the estrogen sensitivity of a tumor. Further study is warranted to determine whether hormonal sensitivity assessed by the use of tamoxifen might serve to select tumors likely to respond to hormonal therapy.

Adult↗
PubMed1994

Precise localization of the genes for glucose phosphate isomerase (GPI), calcium release channel (CRC), hormone-sensitive lipase (LIPE), and growth hormone (GH) in pigs, using nonradioactive in situ hybridization.

Fluorescence in situ hybridization (FISH) was applied, using genomic DNA clones, to precisely localize the genes for GPI, CRC, LIPE, and GH on pig chromosomes. The porcine CRC gene was localized to band 6q12 using both genomic and cDNA clones. The GPI and LIPE genes, which are closely linked to the CRC gene, were also mapped to the same band (6q12), using genomic lambda clones. The mapping data are a refinement of earlier findings, wherein radioactive in situ hybridization was used and the assignments included both the short and long arms. Results of the present study clearly exclude the short arm as the location for the three genes. Further, using a genomic cosmid clone, the GH gene was mapped to band 12p14. Compared to the earlier assignments, which included almost the entire short arm of the chromosome due to the use of radioactive in situ hybridization, the present FISH findings provide a band-specific localization for the gene. A modified, simpler version of the posthybridization trypsin/EDTA banding method is also presented.

Animals↗
PubMed1977

Unchanged hormone sensitivity of rat fat cell adenylate cyclase in uremia.

The sensitivity to hormones of the fat cell adenylate cyclase system was tested in uremic rats and in pair-fed control animals. Basal enzyme activities averaged 1.25 nmoles of cAMP formed per mg protein per 15 min in controls compared to 1.30 nmoles cAMP/mg protein/15 min in fat cell ghosts obtained from uremic rats. NaF caused an approximately 4-fold stimulation of enzyme activities in both systems. It was shown that parathyroid hormone should be included amongst the hormones which act as stimulators of the enzyme system. The responsiveness of the rat fat cell adenylate cyclase system towards saturating concentrations of ACTH, glucagon, epinephrine and parathyroid hormone was not altered in the presence of chronic renal failure.

Adenylyl Cyclases↗
PubMed1997

Suppression of neutral cholesterol ester hydrolase activity by antisense DNA of hormone-sensitive lipase.

In order to investigate the role of the hormone-sensitive lipase (HSL) gene in the activity of neutral cholesterol ester hydrolase (NCEH) from a molecular perspective, Chinese hamster ovary (CHO) cells were transfected with rat antisense hormone-sensitive lipase cDNA, and three different cell lines, designated as anti-HSL, were established. NCEH activity in anti-HSL cells was reduced to approximately 50% of that in control CHO cells. The concentration of cellular esterified cholesterol increased and the concentration of free cholesterol decreased in the anti-HSL cell lines. These results suggest that the HSL gene has a function of NCEH as well.

Animals↗