Involvement of the collagen I-binding motif in the anti-angiogenic activity of pigment epithelium-derived factor

Hosomichi, Jun; Yasui, Norio; Koide, Takao; Soma, Kunimichi; Morita, Ikuo

doi:10.1016/j.bbrc.2005.07.140

Cited by 45 publications

(32 citation statements)

References 20 publications

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“…Thus, we provide here an answer to the widely debatable question of whether PEDF exerts a direct effect on cancer cells and the nature of this effect. Our findings are in agreement with another study that showed lack of PEDF effect on proliferation of cultured HeLa cells but efficient eradication of HeLa xenografts in vivo (34). The lack of the proapoptotic effect of PEDF toward cancer cells could be explained by the higher basal activity of survival pathways or the presence of a distinct, less-specific receptor.…”

Section: Discussionsupporting

confidence: 82%

Pigment Epithelium-derived Factor and Its Phosphomimetic Mutant Induce JNK-dependent Apoptosis and p38-mediated Migration Arrest

Konson

Pradeep

D’Acunto

et al. 2011

Journal of Biological Chemistry

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Pigment epithelium-derived factor (PEDF) is a potent endogenous inhibitor of angiogenesis and a promising anticancer agent. We have previously shown that PEDF can be phosphorylated and that distinct phosphorylations differentially regulate its physiological functions. We also demonstrated that triple phosphomimetic mutant (EEE-PEDF), has significantly increased antiangiogenic activity and is much more efficient than WT-PEDF in inhibiting neovascularization and tumor growth. The enhanced antiangiogenic effect was associated with a direct ability to facilitate apoptosis of tumor-residing endothelial cells (ECs), and subsequently, disruption of intratumoral vascularization. In the present report, we elucidated the molecular mechanism by which EEE-PEDF exerts more profound effects at the cellular level. We found that EEE-PEDF suppresses EC proliferation due to caspase-3-dependent apoptosis and also inhibits migration of the EC much better than WT-PEDF. Although WT-PEDF and EEE-PEDF did not affect proliferation and did not induce apoptosis of cancer cells, these agents efficiently inhibited cancer cell motility, with EEE-PEDF showing a stronger effect. The stronger activity of EEE-PEDF was correlated with a better binding to laminin receptors. Furthermore, the proapoptotic and antimigratory activities of WT-PEDF and EEE-PEDF were found regulated by differential activation of two distinct MAPK pathways, namely JNK and p38, respectively. We show that JNK and p38 phosphorylation is much higher in cells treated with EEE-PEDF. JNK leads to apoptosis of ECs, whereas p38 leads to anti-migratory effect in both EC and cancer cells. These results reveal the molecular signaling mechanism by which the phosphorylated PEDF exerts its stronger antiangiogenic, antitumor activities. Pigment epithelium-derived factor (PEDF)2 is a 46-kDa secreted glycoprotein that can act either as a neurotrophic or an antiangiogenic factor (1, 2). PEDF has been originally identified in the retina; however, it has now become evident that it is expressed throughout the human body and is constantly present in the systemic circulation (3, 4). Studies of the past decade have implicated PEDF in the pathophysiology of a wide range of angiogenesis-associated disorders, including diabetic complications (5), macular degeneration (6), and the growth of many types of solid tumors (7-10). Furthermore, the natural antiangiogenic activity of PEDF, which is far greater than that of any other known endogenously produced factor (2, 11), has turned it into a highly potent therapeutic agent for the inhibition of pathological neovascularization and, therefore, a promising tumor suppressor. To date, a number of studies have shown that exogenous administration of PEDF results in tumor regression, decreased intratumoral microvessel density, and prolonged survival in various animal cancer models (12-15). The underlying molecular mechanism of anticancer activity of PEDF has been under extensive investigation recently (13,16). Yet, the signaling pathways that mediate the effect...

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Section: Discussionsupporting

confidence: 82%

Pigment Epithelium-derived Factor and Its Phosphomimetic Mutant Induce JNK-dependent Apoptosis and p38-mediated Migration Arrest

Konson

Pradeep

D’Acunto

et al. 2011

Journal of Biological Chemistry

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“…Indeed, we showed that PEDF and its mutants preferentially induce apoptosis in endothelial and much less in cancer cells in vivo and do not affect cancer cell survival in vitro, while efficiently inhibiting the growth rate of xenografts originating from these cells. This is in agreement with another study that showed similar effects of PEDF in HeLa cells, although the effect of phosphomimetic mutants of PEDF was not examined there (33). These results suggest that the antiangiogenic activity of PEDF, for example, its ability to affect actively proliferating and migrating endothelial cells, is the main component of its antitumor action.…”

Section: Discussionsupporting

confidence: 90%

Phosphomimetic Mutants of Pigment Epithelium-Derived Factor with Enhanced Antiangiogenic Activity as Potent Anticancer Agents

Konson

Pradeep²,

Seger

2010

Cancer Research

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Pigment epithelium-derived factor (PEDF) is an endogenous inhibitor of angiogenesis and a promising anticancer agent capable of suppressing solid tumor growth in animal cancer models. We have previously shown that PEDF can be phosphorylated and that distinct phosphorylation states of this factor differentially regulate its physiologic function. Here, we report that phosphomimetic mutants of PEDF, which possess significantly increased antiangiogenic activity, are much more efficient than wild-type (WT) PEDF in inhibiting growth and neovascularization in MDA-MB-231 (breast cancer), HCT116 (colon cancer), and U87-MG (glioblastoma) xenograft models. Importantly, the antitumor activity of the phosphomimetic mutants is comparable with that of the established antiangiogenic agent bevacizumab. However, unlike bevacizumab, these compounds act in a vascular endothelial growth factor (VEGF)-independent manner, as they do not affect the levels of VEGF-A mRNA and VEGF receptor 2 phosphorylation. Further immunohistochemical analysis revealed that PEDF mutants affect mainly tumor-residing endothelial cells and prevent the formation of intratumoral vascular network by facilitating endothelial cell apoptosis. It was also found that PEDF mutants reduce survival of endothelial cells in culture much better than WT-PEDF, an effect that is apparent even in the presence of VEGF or basic fibroblast growth factor, and promote much stronger endothelial cell apoptosis. On the other hand, PEDF and its mutants did not affect survival of cultured cancer cells, indicating that the antiangiogenic activity of these agents is the foremost element of the observed antitumor effect. These findings have specific implications on improving the properties of WT-PEDF, which is currently in preclinical development, and encourage the development of PEDF mutants as specific, neovascularization-targeting anticancer agents. Cancer Res; 70(15); 6247-57. ©2010 AACR.

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“…Analyses of its amino acid sequence (34) and its crystal structure (54) have revealed distinct binding sites for ECM components collagen-1 (35,39) and glycosaminoglycans (3), including heparin (59,66) and hyaluronan (6). Binding of PEDF to collagen-1 promotes antiangiogenesis directly (30) or indirectly by disrupting ECM-cell adhesion interactions that are crucial for angiogenesis (66). These studies suggest that the tissue microenvironment, including oxygen levels and ECM composition, influences PEDF expression and function.…”

mentioning

confidence: 99%

Pigment epithelium-derived factor as a multifunctional regulator of wound healing

Wietecha

Król

Michalczyk

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Wietecha MS, Król MJ, Michalczyk ER, Chen L, Gettins PG, DiPietro LA. Pigment epithelium-derived factor as a multifunctional regulator of wound healing. Am J Physiol Heart Circ Physiol 309: H812-H826, 2015. First published July 10, 2015; doi:10.1152/ajpheart.00153.2015.-During dermal wound repair, hypoxia-driven proliferation results in dense but highly permeable, disorganized microvascular networks, similar to those in solid tumors. Concurrently, activated dermal fibroblasts generate an angiopermissive, provisional extracellular matrix (ECM). Unlike cancers, wounds naturally resolve via blood vessel regression and ECM maturation, which are essential for reestablishing tissue homeostasis. Mechanisms guiding wound resolution are poorly understood; one candidate regulator is pigment epithelium-derived factor (PEDF), a secreted glycoprotein. PEDF is a potent antiangiogenic in models of pathological angiogenesis and a promising cancer and cardiovascular disease therapeutic, but little is known about its physiological function. To examine the roles of PEDF in physiological wound repair, we used a reproducible model of excisional skin wound healing in BALB/c mice. We show that PEDF is abundant in unwounded and healing skin, is produced primarily by dermal fibroblasts, binds to resident microvascular endothelial cells, and accumulates in dermal ECM and epidermis. PEDF transcript and protein levels were low during the inflammatory and proliferative phases of healing but increased in quantity and colocalization with microvasculature during wound resolution. Local antibody inhibition of endogenous PEDF delayed vessel regression and collagen maturation during the remodeling phase. Treatment of wounds with intradermal injections of exogenous, recombinant PEDF inhibited nascent angiogenesis by repressing endothelial proliferation, promoted vascular integrity and function, and increased collagen maturity. These results demonstrate that PEDF contributes to the resolution of healing wounds by causing regression of immature blood vessels and stimulating maturation of the vascular microenvironment, thus promoting a return to tissue homeostasis after injury.

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Involvement of the collagen I-binding motif in the anti-angiogenic activity of pigment epithelium-derived factor

Cited by 45 publications

References 20 publications

Pigment Epithelium-derived Factor and Its Phosphomimetic Mutant Induce JNK-dependent Apoptosis and p38-mediated Migration Arrest

Pigment Epithelium-derived Factor and Its Phosphomimetic Mutant Induce JNK-dependent Apoptosis and p38-mediated Migration Arrest

Phosphomimetic Mutants of Pigment Epithelium-Derived Factor with Enhanced Antiangiogenic Activity as Potent Anticancer Agents

Pigment epithelium-derived factor as a multifunctional regulator of wound healing

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