Florine Stettheimer

Wye, Pamela

doi:10.1215/9780822380061-036

M/E/a/N/I/N/G 2000

DOI: 10.1215/9780822380061-036

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Florine Stettheimer

Pamela Wye¹

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2010

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“…Increased serum cholesterol and cholesterol accumulation in atherosclerotic lesions have been long associated to cardiovascular disease (2) and atherosclerosis (3,4), respectively. Abnormal cholesterol accumulation has been also found in some malignancies, such as prostate tumors (5,6). Furthermore, recent studies suggest that inhibition of the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methyl-glutarylcoenzyme A reductase) by long-term statin therapy decreases the incidence of certain tumor types (7,8).…”

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Methyl-β-cyclodextrin Suppresses Hyaluronan Synthesis by Down-regulation of Hyaluronan Synthase 2 through Inhibition of Akt

Kultti

Kärnä

Rilla

et al. 2010

Journal of Biological Chemistry

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Hyaluronan synthases (HAS1-3) are integral plasma membrane proteins that synthesize hyaluronan, a cell surface and extracellular matrix polysaccharide necessary for many biological processes. It has been shown that HAS is partly localized in cholesterol-rich lipid rafts of MCF-7 cells, and cholesterol depletion with methyl-␤-cyclodextrin (M␤CD) suppresses hyaluronan secretion in smooth muscle cells. However, the mechanism by which cholesterol depletion inhibits hyaluronan production has remained unknown. We found that cholesterol depletion from MCF-7 cells by M␤CD inhibits synthesis but does not decrease the molecular mass of hyaluronan, suggesting no major influence on HAS stability in the membrane. The inhibition of hyaluronan synthesis was not due to the availability of HAS substrates UDP-GlcUA and UDP-GlcNAc. Instead, M␤CD specifically down-regulated the expression of HAS2 but not HAS1 or HAS3. Screening of signaling proteins after M␤CD treatment revealed that phosphorylation of Akt and its downstream target p70S6 kinase, both members of phosphoinositide 3-kinase-Akt pathway, were inhibited. Inhibitors of this pathway suppressed hyaluronan synthesis and HAS2 expression in MCF-7 cells, suggesting that the reduced hyaluronan synthesis by M␤CD is due to down-regulation of HAS2, mediated by the phosphoinositide 3-kinase-Akt-mTOR-p70S6K pathway.Cholesterol is an important membrane constituent of mammalian cells, plasma membrane in particular. It decreases the fluidity of the membrane and is a major component of the detergent-resistant membrane microdomains called lipid rafts (1). Increased serum cholesterol and cholesterol accumulation in atherosclerotic lesions have been long associated to cardiovascular disease (2) and atherosclerosis (3, 4), respectively. Abnormal cholesterol accumulation has been also found in some malignancies, such as prostate tumors (5, 6). Furthermore, recent studies suggest that inhibition of the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methyl-glutarylcoenzyme A reductase) by long-term statin therapy decreases the incidence of certain tumor types (7,8).Cellular cholesterol content can be modulated by the cholesterol depleting agent methyl-␤-cyclodextrin (M␤CD) 2 (9). M␤CD disrupts lipid rafts (10) and activates many signaling proteins, like epidermal growth factor receptor (11), extracellular signal-regulated kinase (ERK) (12, 13), p38 (11,14), Src (15), and ␤-catenin (16). On the other hand, M␤CD decreases the growth of MCF-7 breast cancer and A2780 ovarian cancer cells implanted subcutaneously in nude mice (17). In the MCF-7 model M␤CD was even more effective than doxorubicin (17).Hyaluronan, a large glycosaminoglycan mainly present in the extracellular matrix of vertebrates, is composed of repeating disaccharide units containing glucuronic acid (GlcUA) and N-acetylglucosamine (GlcNAc). It is produced at the plasma membrane by three hyaluronan synthases (HAS1-3). HASs use UDP-GlcUA and UDP-GlcNAc as substrates and extrude the forming hyaluronan chain to the extracellu...

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mentioning

confidence: 99%

Methyl-β-cyclodextrin Suppresses Hyaluronan Synthesis by Down-regulation of Hyaluronan Synthase 2 through Inhibition of Akt

Kultti

Kärnä

Rilla

et al. 2010

Journal of Biological Chemistry

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Florine Stettheimer

Cited by 1 publication

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Methyl-β-cyclodextrin Suppresses Hyaluronan Synthesis by Down-regulation of Hyaluronan Synthase 2 through Inhibition of Akt

Methyl-β-cyclodextrin Suppresses Hyaluronan Synthesis by Down-regulation of Hyaluronan Synthase 2 through Inhibition of Akt

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