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Johannes V. Swinnen - One of the best experts on this subject based on the ideXlab platform.
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Androgens and the Lipogenic Switch in Prostate Cancer
Androgen Action in Prostate Cancer, 2009Co-Authors: Johannes V. Swinnen, Koen Brusselmans, Hannelore Heemers, Guido VerhoevenAbstract:Androgens have a major impact on prostate cancer cell biology and modulate a variety of key cellular processes and functions. One of the processes that are most strikingly affected is lipid biosynthesis. Through a unique indirect mechanism that involves activation of the Lipogenic transcription factor SREBP, androgens coordinately stimulate the expression of more than 20 enzymes involved in lipid synthesis, and in this way they affect the entire Lipogenic program in prostate cancer cells. Through additional mechanisms, including the stimulation of an ubiquitin-specific protease that removes the degradation-tag ubiquitin from Lipogenic enzymes such as fatty acid synthase, an even more complex network of regulatory control is created. Progressive deregulation of this network results in a marked overexpression of Lipogenic enzymes, referred to as the Lipogenic switch. This switch typically accompanies the development and progression of prostate cancer and is thought to play an active role in prostate cancer cell biology. In fact, interference with the Lipogenic process impairs proper membrane formation and functioning, halts cell proliferation, and induces cell death selectively in cancer cells. These findings suggest that enhanced lipogenesis in cancer cells is an essential trait of prostate cancer progression and is a promising novel target for antineoplastic intervention.
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rna interference mediated silencing of the acetyl coa carboxylase α gene induces growth inhibition and apoptosis of prostate cancer cells
Cancer Research, 2005Co-Authors: Koen Brusselmans, Guido Verhoeven, Ellen De Schrijver, Johannes V. SwinnenAbstract:Overexpression of Lipogenic enzymes is a common characteristic of many cancers. Thus far, studies aimed at the exploration of Lipogenic enzymes as targets for cancer intervention have focused on fatty acid synthase (FAS), the enzyme catalyzing the terminal steps in fatty acid synthesis. Chemical inhibition or RNA interference (RNAi)–mediated knockdown of FAS consistently inhibits the growth and induces death of cancer cells. Accumulation of the FAS substrate malonyl-CoA has been implicated in the mechanism of cytotoxicity of FAS inhibition. Here, using RNAi technology, we have knocked down the expression of acetyl-CoA carboxylase-α (ACC-α), the enzyme providing the malonyl-CoA substrate. Silencing of the ACC-α gene resulted in a similar inhibition of cell proliferation and induction of caspase-mediated apoptosis of highly Lipogenic LNCaP prostate cancer cells as observed after FAS RNAi. In nonmalignant cells with low Lipogenic activity, no cytotoxic effects of knockdown of ACC-α or FAS were observed. These findings indicate that accumulation of malonyl-CoA is not a prerequisite for cytotoxicity induced by inhibition of tumor-associated lipogenesis and suggest that in addition to FAS, ACC-α is a potential target for cancer intervention.
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Androgens, lipogenesis and prostate cancer
The Journal of Steroid Biochemistry and Molecular Biology, 2004Co-Authors: Johannes V. Swinnen, Koen Brusselmans, Hannelore Heemers, Walter Heyns, Ellen De Schrijver, Tine Van De Sande, Guido VerhoevenAbstract:Both experimental and epidemiological data indicate that androgens are among the main factors controlling the development, maintenance and progression of prostate cancer. Identifying the genes that are regulated by androgens represents a major step towards the elucidation of the mechanisms underlying the impact of androgens on prostate cancer cell biology and is an attractive approach to find novel targets for prostate cancer therapy. Among the genes that have been identified thus far, several genes encode Lipogenic enzymes. Studies aimed at the elucidation of the mechanisms underlying androgen regulation of Lipogenic genes revealed that androgens coordinately stimulate the expression of these genes through interference with the molecular mechanism controlling activation of sterol regulatory element-binding proteins (SREBPs), Lipogenic transcription factors governing cellular lipid homeostasis. The resulting increase in lipogenesis serves the synthesis of key membrane components (phospholipids, cholesterol) and is a major hallmark of cancer cells. Pharmacologic inhibition of lipogenesis or RNA-interference-mediated down-regulation of key Lipogenic genes induces apoptosis in cancer cell lines and reduces tumor growth in xenograft models. While increased lipogenesis is already found in the earliest stages of cancer development (PIN) and initially is androgen-responsive it persists or re-emerges with the development of androgen-independent cancer, indicating that lipogenesis is a fundamental aspect of prostate cancer cell biology and is a potential target for chemoprevention and for antineoplastic therapy in advanced prostate cancer.
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Androgens stimulate coordinated Lipogenic gene expression in normal target tissues in vivo.
Molecular and cellular endocrinology, 2003Co-Authors: Hannelore Heemers, Guido Verhoeven, Walter Heyns, Frank Vanderhoydonc, Tania Roskams, Ishaiahu Shechter, Johannes V. SwinnenAbstract:In prostate cancer cell lines in culture androgens cause a marked and coordinated upregulation of the expression of several Lipogenic genes. Here, using castrated male Wistar rats as an experimental paradigm, we investigated whether coordinated androgen stimulation of Lipogenic gene expression represents a more general physiological regulation in non-cancerous androgen-responsive cells as well. In typical target tissues for androgen action such as the ventral prostate and the lacrimal gland, androgen deprivation resulted in a marked reduction in the mRNA and protein levels of genes involved in fatty acid (fatty acid synthase and acetyl-CoA-carboxylase) and cholesterol synthesis (HMG-CoA-reductase and farnesyl diphosphate synthase). Readministration of testosterone immediately following orchidectomy restored the expression of all four genes. Substitution of testosterone by the non-aromatizable androgen dihydrotestosterone gave rise to comparable changes in the mRNA and protein levels of the Lipogenic genes under investigation, confirming the involvement of the androgen receptor in the observed effects. In support of the coordinate nature of this regulation, androgen-induced upregulation of Lipogenic gene expression is accompanied by an increase in the nuclear content of SREBP, a key Lipogenic transcription factor. Taken together, these findings provide evidence for a coordinate regulation of Lipogenic gene expression not only in prostate cancer cell lines in culture but also in non-cancerous androgen-responsive tissues in vivo.
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androgens stimulate Lipogenic gene expression in prostate cancer cells by activation of the sterol regulatory element binding protein cleavage activating protein sterol regulatory element binding protein pathway
Molecular Endocrinology, 2001Co-Authors: Hannelore Heemers, Guido Verhoeven, Walter Heyns, Bart Maes, Fabienne Foufelle, Johannes V. SwinnenAbstract:Using two independent prostate cancer cell lines (LNCaP and MDA-PCa-2a), we demonstrate that coordinated stimulation of Lipogenic gene expression by androgens is a common phenomenon in androgen-responsive prostate tumor lines and involves activation of the sterol regulatory element-binding protein (SREBP) pathway. We show 1) that in both cell lines, androgens stimulate the expression of fatty acid synthase and hydroxymethylglutaryl-coenzyme A synthase, two key Lipogenic genes representative for the fatty acid and the cholesterol synthesis pathway, respectively; 2) that treatment with androgens results in increased nuclear levels of active SREBP; 3) that the effects of androgens on promoter-reporter constructs derived from both Lipogenic genes (fatty acid synthase and hydroxymethylglutaryl-coenzyme A synthase) depend on the presence of intact SREBP-binding sites; and 4) that cotransfection with dominant-negative forms of SREBPs abolishes the effects of androgens. Related to the mechanism underlying androge...
Julian Swierczynski - One of the best experts on this subject based on the ideXlab platform.
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Up-regulation of Lipogenic enzyme genes expression in inguinal white adipose tissue of female rats by progesterone.
The Journal of steroid biochemistry and molecular biology, 2012Co-Authors: Ewa Stelmanska, Julian SwierczynskiAbstract:Abstract Contradictory results have been published regarding the influence of progesterone on lipids metabolism in adipose tissue. The aim of the present work was to elucidate whether progesterone administration in the setting of an experimental model influences Lipogenic enzyme genes expression, body and adipose tissue mass. The results presented here indicate that the elevated blood progesterone concentration was associated with significant increase in Lipogenic enzyme genes expression in inguinal adipose tissue of females. The rise in the expression of Lipogenic enzyme genes was associated with an increase in sterol regulatory element binding transcription factor 1 (Srebf1) and S14 genes expression. Mifepristone, a specific antagonist of progesterone receptor, abolished progesterone's effect on body mass, inguinal fat mass, and Lipogenic enzyme genes expression in inguinal adipose tissue. No significant changes were found in the expression of Lipogenic enzyme genes, Srebf1 and S14 genes in perirenal white adipose tissue of females. The elevated blood progesterone concentration was associated with the increase in body and inguinal white adipose tissue mass of females. In males, elevated blood progesterone concentration had no effect on the Lipogenic enzyme genes expression and on body and fat mass. In conclusion, we demonstrate that a chronic increase in serum progesterone concentration in females was associated with up-regulation of Lipogenic enzyme genes expression in inguinal adipose tissue. Up-regulation of Srebf1 and S14 genes expression following progesterone administration suggests that products of these genes might be involved in the regulation of Lipogenic enzyme genes expression by progesterone. The stimulatory effect of progesterone on Lipogenic enzyme genes expression in inguinal adipose tissue seems to be specific as it was reversed by specific antagonist of progesterone receptor.
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Chronic food restriction up-regulates 11-β-hydroxysteroid dehydrogenase
Central European Journal of Biology, 2011Co-Authors: Tomasz Sledzinski, Ewa Stelmanska, Jacek Turyn, Malgorzata Presler, Jerzy Klimek, Julian SwierczynskiAbstract:Corticosterone — product of 11-β-hydroxysteroid dehydrogenase type I (11βHSD1) stimulates adipocytes differentiation and activates Lipogenic enzymes gene expression in white adipose tissue (WAT) of rats. The aim of the study was to examine the effect of chronic food restriction, often practised by obese individuals trying to lose body mass, on: a) 11βHSD1 gene expression, b) expression of genes associated with adipocyte differentiation (PPARg, SREBP-1, adiponectin), and c) expression of genes associated with lipogenesis in WAT of rats. Two-month old rats were divided into a control and a food restricted group obtaining 50% of food consumed by controls for 30 days. mRNA levels of studied genes in perirenal WAT were analysed by real-time PCR. 11βHSD1 and Lipogenic enzymes activities were measured by radiometric conversion assay and by spectrophotometric assay respectively. Food restriction caused significant increase of 11βHSD1, PPARg, SREBP1, adiponectin and Lipogenic enzymes mRNA levels in perirenal WAT. 11βHSD1 and some Lipogenic enzymes activities were also increased by food restriction. The coordinated up-regulation of 11βHSD1, and genes associated with adipocyte differentiation and lipogenesis by food restriction suggests that such nutritional condition shifts WAT metabolism, that would permit this tissue to synthesize and accumulate triacylglycerols immediately after refeeding.
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Leptin decreases Lipogenic enzyme gene expression through modification of SREBP-1c gene expression in white adipose tissue of aging rats
Metabolism: clinical and experimental, 2005Co-Authors: Anna Nogalska, Elzbieta Sucajtys-szulc, Julian SwierczynskiAbstract:Aging is associated with a significant reduction of Lipogenic enzyme gene expression and lipogenesis in white adipose tissue (WAT). The age-related increase of lep gene expression could be, in part, responsible for these changes. Considering that sterol regulatory element binding protein 1c (SREBP-1c) plays an important role in regulation of Lipogenic enzyme gene expression, it is likely that the age-related decrease of WAT Lipogenic potential could be a consequence of the inhibition of SREBP-1c gene expression by leptin. We determined whether the increase of lep gene expression would account for the age-related decrease in SREBP-1c and its direct target, main Lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), by assaying the messenger RNA (mRNA) levels of SREBP-1c, FAS, ACC , and leptin in WAT of 2-month-old (young) and 20-month-old (old) rats. Leptin mRNA level was much higher in the old animals, whereas in contrast, old rats displayed much lower mRNA levels of SREBP-1c and Lipogenic enzymes. Moreover, experimentally increased plasma leptin concentration in young rats to the value observed in old rats resulted in the decrease of SREBP-1c, FAS, and ACC mRNA levels in WAT. Thus, the increase of lep gene expression could, in part, account for the reduced SREBP-1c gene expression and, consequently, the diminished Lipogenic activity in WAT of old animals.
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The age-related inverse relationship between ob and Lipogenic enzymes genes expression in rat white adipose tissue.
Experimental gerontology, 2003Co-Authors: Anna Nogalska, Areta Pankiewicz, Elzbieta Goyke, Julian SwierczynskiAbstract:To determine whether increase of serum leptin (the known natural inhibitor of Lipogenic enzymes gene expression) concentration would account for the age-related decrease in lipogenesis (a) serum leptin concentration; (b) leptin mRNA abundance; (c) the rate of fatty acid synthesis in vivo; (d) Lipogenic enzymes activity and (e) mRNA levels were assayed in white adipose tissue (WAT) of male young and old rats. We found that leptin mRNA abundance in WAT and serum leptin concentration was much lower in young than in old animals. In contrast, the rate of fatty acid synthesis in WAT was much higher in young animals. The old rats displayed much lower Lipogenic enzymes activities (acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), ATP-citrate lyase (ACL), malic enzyme (ME), glucose 6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dedydrogenase 6PGDH) and mRNA abundance as compared to young rats. Considering the inverse relationship between serum leptin concentration and Lipogenic enzymes genes expression and known inhibitory effect of leptin on Lipogenic enzymes gene expression, one can conclude that the increase of ob gene expression could at least partly account for the reduced WAT Lipogenic enzymes genes expression in old animals.
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Increase of Lipogenic enzyme mRNA levels in rat white adipose tissue after multiple cycles of starvation-refeeding.
Metabolism: clinical and experimental, 2001Co-Authors: Joanna Karbowska, Zdzislaw Kochan, Julian SwierczynskiAbstract:Recently, we have found that despite the significant reduction of body weight after multiple starvation-refeeding cycles, white adipose tissue (WAT) exhibits surprisingly high rates of lipogenesis and Lipogenic enzyme activities. The purpose of this study was to determine the response of WAT Lipogenic enzyme mRNAs of rats subjected to multiple cycles of 3 days fasting and 3 days of refeeding. Despite the body weight reduction, significant increase of Lipogenic enzymes (ie, fatty acid synthase [FAS], acetyl-coenzyme A [CoA] carboxylase [ACC], adenosine triphosphate (ATP)-citrate lyase [ACL], NADP-linked malic enzyme [ME], and glucose 6-phosphate dehydrogenase [G6PDH]) mRNAs in WAT was found after multiple cycles of starvation-refeeding of rats on standard laboratory diet. These findings, together with the results published recently, indicate that multiple cycles of starvation-refeeding cause the increased lipogenesis in WAT by upregulation of the Lipogenic enzymes gene expression.
James M Ntambi - One of the best experts on this subject based on the ideXlab platform.
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stearoyl coa desaturase 1 gene expression is necessary for fructose mediated induction of Lipogenic gene expression by sterol regulatory element binding protein 1c dependent and independent mechanisms
Journal of Biological Chemistry, 2004Co-Authors: Makoto Miyazaki, Agnieszka Dobrzyn, Weng Chi Man, Kiki Chu, Harini Sampath, Hyoun Ju Kim, James M NtambiAbstract:Stearoyl-CoA desaturase (SCD) synthesizes oleate necessary for the biosynthesis of triglycerides and other lipids. Mice with a targeted disruption of the SCD1 gene are deficient in tissue oleate and have reduced expression of the sterol regulatory element-binding protein (SREBP) and its target genes. The SREBP-1c isoform is a known mediator of insulin action on hepatic gene expression, but its transcriptional effects due to glucose or fructose are still unclear. We found that fructose compared with glucose is a stronger inducer of SREBP-1c and Lipogenic gene expression, causing a dramatic increase in hepatic triglyceride levels. However, when fed to the SCD1-/- mice, fructose failed to induce SREBP-1 or Lipogenic genes and the triglyceride levels were not increased. Instead fructose feeding caused a decrease in hepatic glycogen and plasma glucose levels. The induction of SREBP-1 and Lipogenic gene expression as well as the levels of liver triglycerides, glycogen, and plasma glucose was partially restored when the fructose diet was supplemented with very high levels of oleate (20% by weight) but not with palmitate, stearate, or linoleate. Fructose in a long term feeding induced the expression of SCD1 and that of other Lipogenic genes in the liver of SREBP-1c-/- mice, and a further increase in expression of these genes occurred when the fructose diet was supplemented with oleate. Our observations demonstrated that oleate produced by SCD is necessary for fructose-mediated induction of Lipogenic gene expression through SREBP-1c-dependent and -independent mechanisms and suggested that SCD1 gene expression is important in lipid and carbohydrate homeostasis.
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a Lipogenic diet in mice with a disruption of the stearoyl coa desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis
Journal of Lipid Research, 2001Co-Authors: Makoto Miyazaki, Youngcheul Kim, James M NtambiAbstract:Stearoyl-CoA desaturase (SCD) catalyzes the de novo biosynthesis of oleate and palmitoleate, which are the major fatty acids found in triglycerides, cholesteryl esters, and phospholipids. A high carbohydrate (Lipogenic) diet induces Lipogenic gene expression by sterol regulatory element binding protein 1 (SREBP-1c)-mediated gene transcription, leading to an increase in the synthesis of triglycerides. The Lipogenic diet fed to mice with a null mutation in the SCD1 gene (SCD-/-) fails to induce the synthesis of triglycerides in liver, despite the induction of expression of SREBP-1 and its target genes, fatty acid synthase and glycerol-3-phosphate acyltransferase. The Lipogenic diet led to a decrease in the levels of triglyceride, but an increase in the level of cholesteryl esters of saturated fatty acids. Feeding a Lipogenic diet supplemented with high levels of oleate to the SCD-/- mice resulted in incorporation of oleate in the liver of SCD-/- mice, but failed to restore triglycerides to the levels in the normal mouse. Triglyceride synthesis, as measured by the incorporation of [(3)H]glycerol, was dramatically reduced in the liver of SCD-/- mouse fed a Lipogenic diet compared with the normal mouse. These observations demonstrate that induction of triglyceride synthesis is highly dependent on SCD1 gene expression.
Hitoshi Shimano - One of the best experts on this subject based on the ideXlab platform.
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Co-ordinate activation of Lipogenic enzymes in hepatocellular carcinoma.
European journal of cancer (Oxford England : 1990), 2005Co-Authors: Naoya Yahagi, Hitoshi Shimano, Kiyoshi Hasegawa, Kenichi Ohashi, Takashi Matsuzaka, Yuho Najima, Motohiro Sekiya, Sachiko Tomita, Hiroaki Okazaki, Yoshiaki TamuraAbstract:Hepatocellular carcinoma is a very common neoplastic disease in countries where hepatitis viruses B and/or C are prevalent. Small hepatocellular carcinoma lesions detected by ultrasonography at an early stage are often hyperechoic because they are composed of well-differentiated cancer cells that are rich in triglyceride droplets. The triglyceride content of hepatocytes depends in part on the rate of lipogenesis. Key Lipogenic enzymes, such as fatty acid synthase, are co-ordinately regulated at the transcriptional level. We therefore examined the mRNA expression of Lipogenic enzymes in human hepatocellular carcinoma samples from 10 patients who had undergone surgical resection. All of the samples exhibited marked elevation of expression of mRNA for Lipogenic enzymes, such as fatty acid synthase, acetyl-CoA carboxylase and ATP citrate lyase, compared with surrounding non-cancerous liver tissue. In contrast, the changes in mRNA expression of SREBP-1, a transcription factor that regulates a battery of Lipogenic enzymes, did not show a consistent trend. In some cases where SREBP-1 was elevated, the main contributing isoform was SREBP-1c rather than SREBP-1a. Thus, Lipogenic enzymes are markedly induced in hepatocellular carcinomas, and in some cases SREBP-1c is involved in this activation.
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sterol regulatory element binding protein 1 as a dominant transcription factor for gene regulation of Lipogenic enzymes in the liver
Trends in Cardiovascular Medicine, 2000Co-Authors: Hitoshi ShimanoAbstract:Sterol regulatory element-binding proteins (SREBPs) are basic helix-loop-helix (bHLH) type transcription factors that control expression of genes involved in biosynthesis of cholesterol and fatty acids. Dietary studies with normal, transgenic, and knockout mice have established SREBP-1 as a dominant transcription factor regulating gene expression of Lipogenic enzyme in the liver. Polyunsaturated fatty acids inhibit hepatic Lipogenic enzymes through suppressing SREBP-1. Whereas SREBP-2 exerts sterol regulation through cleavage of the membrane-bound precursor protein to liberate the active nuclear form into the nucleus, SREBP-1 controls Lipogenic enzymes by self-regulating its own transcription level. Promoter analysis of the SREBP-1 gene will be important to clarify the mechanism of nutritional regulation of Lipogenic genes.
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sterol regulatory element binding protein 1 as a key transcription factor for nutritional induction of Lipogenic enzyme genes
Journal of Biological Chemistry, 1999Co-Authors: Hitoshi Shimano, Naoya Yahagi, Yoshiaki Tamura, Yoko Iizuka, Ken Ohashi, Michiyo Amemiyakudo, Alyssa H Hasty, Junichi Osuga, Futoshi Shionoiri, Kenji HaradaAbstract:Abstract To elucidate the physiological role of sterol regulatory element-binding protein-1 (SREBP-1), the hepatic mRNA levels of genes encoding various Lipogenic enzymes were estimated in SREBP-1 gene knockout mice after a fasting-refeeding treatment, which is an established dietary manipulation for the induction of Lipogenic enzymes. In the fasted state, the mRNA levels of all Lipogenic enzymes were consistently low in both wild-type andSREBP-1 −/− mice. However, the absence of SREBP-1 severely impaired the marked induction of hepatic mRNAs of fatty acid synthetic genes, such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase, that was observed upon refeeding in the wild-type mice. Furthermore, the refeeding responses of other Lipogenic enzymes, glycerol-3-phosphate acyltransferase, ATP citrate lyase, malic enzyme, glucose-6-phosphate dehydrogenase, and S14 mRNAs, were completely abolished inSREBP-1 −/− mice. In contrast, mRNA levels for cholesterol biosynthetic genes were elevated in the refedSREBP-1 −/− livers accompanied by an increase in nuclear SREBP-2 protein. When fed a high carbohydrate diet for 14 days, the mRNA levels for these Lipogenic enzymes were also strikingly lower in SREBP-1 −/− mice than those in wild-type mice. These data demonstrate that SREBP-1 plays a crucial role in the induction of lipogenesis but not cholesterol biosynthesis in liver when excess energy by carbohydrates is consumed.
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sterol regulatory element binding protein 1 as a key transcription factor for nutritional induction of Lipogenic enzyme genes
Journal of Biological Chemistry, 1999Co-Authors: Hitoshi Shimano, Naoya Yahagi, Yoshiaki Tamura, Yoko Iizuka, Ken Ohashi, Michiyo Amemiyakudo, Alyssa H Hasty, Junichi Osuga, Futoshi Shionoiri, Kenji HaradaAbstract:Abstract To elucidate the physiological role of sterol regulatory element-binding protein-1 (SREBP-1), the hepatic mRNA levels of genes encoding various Lipogenic enzymes were estimated in SREBP-1 gene knockout mice after a fasting-refeeding treatment, which is an established dietary manipulation for the induction of Lipogenic enzymes. In the fasted state, the mRNA levels of all Lipogenic enzymes were consistently low in both wild-type andSREBP-1 −/− mice. However, the absence of SREBP-1 severely impaired the marked induction of hepatic mRNAs of fatty acid synthetic genes, such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase, that was observed upon refeeding in the wild-type mice. Furthermore, the refeeding responses of other Lipogenic enzymes, glycerol-3-phosphate acyltransferase, ATP citrate lyase, malic enzyme, glucose-6-phosphate dehydrogenase, and S14 mRNAs, were completely abolished inSREBP-1 −/− mice. In contrast, mRNA levels for cholesterol biosynthetic genes were elevated in the refedSREBP-1 −/− livers accompanied by an increase in nuclear SREBP-2 protein. When fed a high carbohydrate diet for 14 days, the mRNA levels for these Lipogenic enzymes were also strikingly lower in SREBP-1 −/− mice than those in wild-type mice. These data demonstrate that SREBP-1 plays a crucial role in the induction of lipogenesis but not cholesterol biosynthesis in liver when excess energy by carbohydrates is consumed.
Guido Verhoeven - One of the best experts on this subject based on the ideXlab platform.
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Androgens and the Lipogenic Switch in Prostate Cancer
Androgen Action in Prostate Cancer, 2009Co-Authors: Johannes V. Swinnen, Koen Brusselmans, Hannelore Heemers, Guido VerhoevenAbstract:Androgens have a major impact on prostate cancer cell biology and modulate a variety of key cellular processes and functions. One of the processes that are most strikingly affected is lipid biosynthesis. Through a unique indirect mechanism that involves activation of the Lipogenic transcription factor SREBP, androgens coordinately stimulate the expression of more than 20 enzymes involved in lipid synthesis, and in this way they affect the entire Lipogenic program in prostate cancer cells. Through additional mechanisms, including the stimulation of an ubiquitin-specific protease that removes the degradation-tag ubiquitin from Lipogenic enzymes such as fatty acid synthase, an even more complex network of regulatory control is created. Progressive deregulation of this network results in a marked overexpression of Lipogenic enzymes, referred to as the Lipogenic switch. This switch typically accompanies the development and progression of prostate cancer and is thought to play an active role in prostate cancer cell biology. In fact, interference with the Lipogenic process impairs proper membrane formation and functioning, halts cell proliferation, and induces cell death selectively in cancer cells. These findings suggest that enhanced lipogenesis in cancer cells is an essential trait of prostate cancer progression and is a promising novel target for antineoplastic intervention.
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rna interference mediated silencing of the acetyl coa carboxylase α gene induces growth inhibition and apoptosis of prostate cancer cells
Cancer Research, 2005Co-Authors: Koen Brusselmans, Guido Verhoeven, Ellen De Schrijver, Johannes V. SwinnenAbstract:Overexpression of Lipogenic enzymes is a common characteristic of many cancers. Thus far, studies aimed at the exploration of Lipogenic enzymes as targets for cancer intervention have focused on fatty acid synthase (FAS), the enzyme catalyzing the terminal steps in fatty acid synthesis. Chemical inhibition or RNA interference (RNAi)–mediated knockdown of FAS consistently inhibits the growth and induces death of cancer cells. Accumulation of the FAS substrate malonyl-CoA has been implicated in the mechanism of cytotoxicity of FAS inhibition. Here, using RNAi technology, we have knocked down the expression of acetyl-CoA carboxylase-α (ACC-α), the enzyme providing the malonyl-CoA substrate. Silencing of the ACC-α gene resulted in a similar inhibition of cell proliferation and induction of caspase-mediated apoptosis of highly Lipogenic LNCaP prostate cancer cells as observed after FAS RNAi. In nonmalignant cells with low Lipogenic activity, no cytotoxic effects of knockdown of ACC-α or FAS were observed. These findings indicate that accumulation of malonyl-CoA is not a prerequisite for cytotoxicity induced by inhibition of tumor-associated lipogenesis and suggest that in addition to FAS, ACC-α is a potential target for cancer intervention.
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Androgens, lipogenesis and prostate cancer
The Journal of Steroid Biochemistry and Molecular Biology, 2004Co-Authors: Johannes V. Swinnen, Koen Brusselmans, Hannelore Heemers, Walter Heyns, Ellen De Schrijver, Tine Van De Sande, Guido VerhoevenAbstract:Both experimental and epidemiological data indicate that androgens are among the main factors controlling the development, maintenance and progression of prostate cancer. Identifying the genes that are regulated by androgens represents a major step towards the elucidation of the mechanisms underlying the impact of androgens on prostate cancer cell biology and is an attractive approach to find novel targets for prostate cancer therapy. Among the genes that have been identified thus far, several genes encode Lipogenic enzymes. Studies aimed at the elucidation of the mechanisms underlying androgen regulation of Lipogenic genes revealed that androgens coordinately stimulate the expression of these genes through interference with the molecular mechanism controlling activation of sterol regulatory element-binding proteins (SREBPs), Lipogenic transcription factors governing cellular lipid homeostasis. The resulting increase in lipogenesis serves the synthesis of key membrane components (phospholipids, cholesterol) and is a major hallmark of cancer cells. Pharmacologic inhibition of lipogenesis or RNA-interference-mediated down-regulation of key Lipogenic genes induces apoptosis in cancer cell lines and reduces tumor growth in xenograft models. While increased lipogenesis is already found in the earliest stages of cancer development (PIN) and initially is androgen-responsive it persists or re-emerges with the development of androgen-independent cancer, indicating that lipogenesis is a fundamental aspect of prostate cancer cell biology and is a potential target for chemoprevention and for antineoplastic therapy in advanced prostate cancer.
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Androgens stimulate coordinated Lipogenic gene expression in normal target tissues in vivo.
Molecular and cellular endocrinology, 2003Co-Authors: Hannelore Heemers, Guido Verhoeven, Walter Heyns, Frank Vanderhoydonc, Tania Roskams, Ishaiahu Shechter, Johannes V. SwinnenAbstract:In prostate cancer cell lines in culture androgens cause a marked and coordinated upregulation of the expression of several Lipogenic genes. Here, using castrated male Wistar rats as an experimental paradigm, we investigated whether coordinated androgen stimulation of Lipogenic gene expression represents a more general physiological regulation in non-cancerous androgen-responsive cells as well. In typical target tissues for androgen action such as the ventral prostate and the lacrimal gland, androgen deprivation resulted in a marked reduction in the mRNA and protein levels of genes involved in fatty acid (fatty acid synthase and acetyl-CoA-carboxylase) and cholesterol synthesis (HMG-CoA-reductase and farnesyl diphosphate synthase). Readministration of testosterone immediately following orchidectomy restored the expression of all four genes. Substitution of testosterone by the non-aromatizable androgen dihydrotestosterone gave rise to comparable changes in the mRNA and protein levels of the Lipogenic genes under investigation, confirming the involvement of the androgen receptor in the observed effects. In support of the coordinate nature of this regulation, androgen-induced upregulation of Lipogenic gene expression is accompanied by an increase in the nuclear content of SREBP, a key Lipogenic transcription factor. Taken together, these findings provide evidence for a coordinate regulation of Lipogenic gene expression not only in prostate cancer cell lines in culture but also in non-cancerous androgen-responsive tissues in vivo.
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androgens stimulate Lipogenic gene expression in prostate cancer cells by activation of the sterol regulatory element binding protein cleavage activating protein sterol regulatory element binding protein pathway
Molecular Endocrinology, 2001Co-Authors: Hannelore Heemers, Guido Verhoeven, Walter Heyns, Bart Maes, Fabienne Foufelle, Johannes V. SwinnenAbstract:Using two independent prostate cancer cell lines (LNCaP and MDA-PCa-2a), we demonstrate that coordinated stimulation of Lipogenic gene expression by androgens is a common phenomenon in androgen-responsive prostate tumor lines and involves activation of the sterol regulatory element-binding protein (SREBP) pathway. We show 1) that in both cell lines, androgens stimulate the expression of fatty acid synthase and hydroxymethylglutaryl-coenzyme A synthase, two key Lipogenic genes representative for the fatty acid and the cholesterol synthesis pathway, respectively; 2) that treatment with androgens results in increased nuclear levels of active SREBP; 3) that the effects of androgens on promoter-reporter constructs derived from both Lipogenic genes (fatty acid synthase and hydroxymethylglutaryl-coenzyme A synthase) depend on the presence of intact SREBP-binding sites; and 4) that cotransfection with dominant-negative forms of SREBPs abolishes the effects of androgens. Related to the mechanism underlying androge...