Evidence That the Serum Inhibitor of Hyaluronidase May Be a Member of the Inter-α-inhibitor Family

Mio, Kazuhiro; Carrette, Odile; Maibach, Howard I.; Stern, Robert

doi:10.1074/jbc.m005428200

Cited by 62 publications

(46 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…dition to inhibiting hyaluronidases (51) and ADAMs (44). Our data propose a possible molecular mechanism for prevention and treatment of malignant tumors through the therapeutic use of a statin agent to lower cholesterol.…”

Section: Discussionmentioning

confidence: 96%

Low Cholesterol Triggers Membrane Microdomain-dependent CD44 Shedding and Suppresses Tumor Cell Migration

Murai

Maruyama

Mio

et al. 2011

Journal of Biological Chemistry

Self Cite

157

146

View full text Add to dashboard Cite

CD44 is a cell surface adhesion molecule for hyaluronan and is implicated in tumor invasion and metastasis. Proteolytic cleavage of CD44 plays a critical role in the migration of tumor cells and is regulated by factors present in the tumor microenvironment, such as hyaluronan oligosaccharides and epidermal growth factor. However, molecular mechanisms underlying the proteolytic cleavage on membranes remain poorly understood. In this study, we demonstrated that cholesterol depletion with methyl-␤-cyclodextrin, which disintegrates membrane lipid rafts, enhances CD44 shedding mediated by a disintegrin and metalloproteinase 10 (ADAM10) and that cholesterol depletion disorders CD44 localization to the lipid raft. We also evaluated the effect of long term cholesterol reduction using a statin agent and demonstrated that statin enhances CD44 shedding and suppresses tumor cell migration on a hyaluronan-coated substrate. Our results indicate that membrane lipid organization regulates CD44 shedding and propose a possible molecular mechanism by which cholesterol reduction might be effective for preventing and treating the progression of malignant tumors.CD44 is a cell surface receptor for several extracellular matrix components, including hyaluronan (1), and is implicated in a wide variety of biological processes, including cell migration (2) and tumor metastasis (3). The migratory properties of invasive tumor cells are affected both by the interaction between their adhesion molecules and the surrounding extracellular matrices and by growth factor signaling (4). The proteolytic ectodomain cleavage and release (shedding) of membrane proteins is a critical regulatory step in both physiological and pathological processes (5, 6).Recently, physiological inducers of CD44 shedding have been identified; hyaluronan small fragments, frequently detected in association with pathological conditions including cancer (7), induce CD44 shedding from tumor cells (8). Intracellular signaling via Rac GTPase, elicited by CD44 engagement, leads to ADAM 2 (a disintegrin and metalloproteinase)-mediated CD44 shedding and tumor cell migration (9). A prominent abnormality of tumor cells such as gliomas is the overexpression of the EGF receptor (10), and EGF induces the shedding of CD44 (11). Although the molecular mechanisms underlying CD44 shedding induced by spatio-temporally ordered intracellular signaling in the tumor microenvironment have been partly clarified (9, 11), the mechanism that triggers CD44 shedding on the membrane is not yet understood.Lipid rafts, which are microdomains of the plasma membrane that are rich in cholesterol and sphingolipids (12), are thought to exhibit a liquid-ordered phase floating in the liquid-disordered matrix of the plasma membrane. Recent studies have confirmed the importance of lipid rafts and their associated proteins, including CD44, in cancer progression (13). A number of reports have shown that CD44 is present in lipid rafts (14 -18). Recently, several reports have demonstrated that lipid rafts play a cruci...

show abstract

Section: Discussionmentioning

confidence: 96%

Low Cholesterol Triggers Membrane Microdomain-dependent CD44 Shedding and Suppresses Tumor Cell Migration

Murai

Maruyama

Mio

et al. 2011

Journal of Biological Chemistry

Self Cite

157

146

View full text Add to dashboard Cite

show abstract

“…Serum inhibitors of hyaluronidase activity have recently been identified, but remain largely uncharacterized. 44 These may complicate the interpretations based on activity data, although it is likely that the conditions used for zymography should remove such inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Hyaluronidase gene profiling and role of HYAL‐1 overexpression in an orthotopic model of prostate cancer

Patel¹,

Turner²,

Stubberfield³

et al. 2001

Intl Journal of Cancer

View full text Add to dashboard Cite

The mRNA levels of hyal-1, hyal-2, LUCA3 and PH20, the 4 hyaluronidases with demonstrated endoglucosaminidase activity, were extensively profiled in normal and tumor tissues and cell lines, using dot blot analysis and quantitative PCR. In normal tissues, hyal-1, hyal-2 and LUCA3 all showed unique patterns of mRNA expression, but were generally of widespread distribution, whereas PH20 mRNA was restricted to testes. In a small set of breast tumor samples, no elevations in hyal-1, hyal-2 or LUCA3 mRNA were seen. Hyaluronidase activity measured by a novel assay or zymography was also not elevated in sera from a number of breast cancer patients, compared to sera from normal volunteers. In ex vivo xenograft tumor cell lines, however, hyal-1 or hyal-2 mRNA levels were frequently elevated, whereas LUCA3 was only infrequently elevated and PH20 not at all. The hyaluronidases are a family of degradative endoglucosaminidase enzymes 1 whose substrate, hyaluronic acid (HA), is a major constituent of the extracellular matrix (ECM). 2 Cellular interactions with the underlying ECM are crucial in development, 3 for the maintenance of normal cellular functions and in response to injury and infection. In situations where malignant cell growth and subsequent metastasis occur, the degradation of the ECM is required. HA, a large polysaccharide of approximately ten thousand disaccharide repeats, is known to inhibit cell differentiation, promote proliferation, regulate cell motility and HA synthesis occurs before mitosis. 1 Increased serum or tissue associated levels of HA have been correlated with tumor progression 2 and metastatic behavior. 4 In some types of cancer such as bladder, breast and colorectal, the serum levels of HA have been found to be of prognostic value, 5-8 although conflicting results have been obtained from patients with breast cancer. 9 The hyaluronidases that degrade HA have also been implicated in tumor progression and metastasis, as well as angiogenesis. 10 Hyaluronidase-1 (hyal-1) was originally isolated from human plasma, has a pH optimum of 3.8 and cleaves HA to small (Ͻ20 kDa) MW fragments. 11 Hyaluronidase-2 (hyal-2) is also an acidactive enzyme that digests HA polymers down to 20 kDa sizes. 12 Hyal-2 has been shown to be located in lysosomes 12 but is also reported to be a GPI-anchored cell surface protein. 13 PH20 was identified as a GPI linked sperm acrosomal enzyme with a neutral pH optimum and cleaves HA to smaller (Ͻ20 kDa) MW fragments. 1 More recently, the hyaluronidase LUCA3 (Barry et al., in preparation) and meningioma expressed antigen 5 (MGEA5, chromosome 10) have also been shown to have activity at neutral pH. 14 Hyal-4 and the pseudogene Hyal-P1, both of which co-localize to chromosome 7q31.3 with PH20, 15 have not yet been demonstrated to possess enzymatic activities.Elevated mRNA levels or increased hyaluronidase enzymatic activity have been associated with invasion and metastasis for ovarian and endometrial cancers, 16 progression of prostate cancer, 17 bladder cancer, 18 colorectal carcino...

show abstract

“…Hyaluronidase-1 is also known as LUCA-1 defined by functional tumor suppressor activity (9). The activity of hyaluronidase-1 in the serum is suppressed by IaI, a potent inhibitor of hyaluronidase (10).…”

Section: Introductionmentioning

confidence: 99%

Magnetic Resonance Imaging Visualization of Hyaluronidase in Ovarian Carcinoma

et al. 2005

Self Cite

View full text Add to dashboard Cite

Hyaluronan, a high molecular weight, negatively charged polysaccharide, is a major constituent of the extracellular matrix. High molecular weight hyaluronan is antiangiogenic, but its degradation by hyaluronidase generates proangiogenic breakdown products. Thus, by expression of hyaluronidase, cancer cells can tilt the angiogenic balance of their microenvironment. Indeed, hyaluronidase-mediated breakdown of hyaluronan correlates with aggressiveness and invasiveness of ovarian cancer metastasis and with tumor angiogenesis. The goal of this work was to develop a novel smart contrast material for detection of hyaluronidase activity by magnetic resonance imaging (MRI). Gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) covalently linked to hyaluronan on the surface of agarose beads showed attenuated relaxivity. Hyaluronidase, either purified from bovine testes or secreted by ES-2 and OVCAR-3 human epithelial ovarian carcinoma cells, activated the hyaluronan-GdDTPA-beads by rapidly altering the R 1 and R 2 relaxation rates. The change in relaxation rates was consistent with the different levels of biologically active hyaluronidase secreted by those cells. Hyaluronan-GdDTPAbeads were further used for demonstration of MRI detection of hyaluronidase activity in the proximity of s.c. ES-2 ovarian carcinoma tumors in nude mice. Thus, hyaluronan-GdDTPAbeads could allow noninvasive molecular imaging of hyaluronidase-mediated tilt of the peritumor angiogenic balance. (Cancer Res 2005; 65(22): 10316-23)

show abstract

Evidence That the Serum Inhibitor of Hyaluronidase May Be a Member of the Inter-α-inhibitor Family

Cited by 62 publications

References 68 publications

Low Cholesterol Triggers Membrane Microdomain-dependent CD44 Shedding and Suppresses Tumor Cell Migration

Low Cholesterol Triggers Membrane Microdomain-dependent CD44 Shedding and Suppresses Tumor Cell Migration

Hyaluronidase gene profiling and role of HYAL‐1 overexpression in an orthotopic model of prostate cancer

Magnetic Resonance Imaging Visualization of Hyaluronidase in Ovarian Carcinoma

Contact Info

Product

Resources

About