Revisiting the biological roles of PAI2 (SERPINB2) in cancer

Croucher, David R.; Saunders, Darren N.; Lobov, Sergei; Ranson, Marie

doi:10.1038/nrc2400

Cited by 178 publications

(226 citation statements)

References 150 publications

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“…Reduced expression of TSP-1 is an important component of the angiogenic switch, and decrease in its expression facilitates growth of several tumor types, including bladder, breast, and ovarian cancer, fibrosarcoma, and glioblastoma (18,19,22). PAI-2 is one of the two major physiological inhibitors of urokinase plasminogen activator, which has been shown to promote invasion and metastasis in various cancer types (20). Strikingly, a number of studies indicated that higher PAI-2 expression in tumors is linked with prolonged survival, decreased metastasis or decreased tumor size (20).…”

Section: Discussionmentioning

confidence: 99%

“…PAI-2 is one of the two major physiological inhibitors of urokinase plasminogen activator, which has been shown to promote invasion and metastasis in various cancer types (20). Strikingly, a number of studies indicated that higher PAI-2 expression in tumors is linked with prolonged survival, decreased metastasis or decreased tumor size (20). Because access to vasculature is a critical component to metastasis, kinases that increase the angiogenic potential of tumor cells would be expected to increase their metastatic potential as well.…”

Section: Discussionmentioning

confidence: 99%

“…Among the 13 wound healing genes regulated by GRK3, we focused on two genes, thrombospondin-1 (TSP-1; THBS1) and plasminogen activator inhibitor 2 (PAI-2; SERPINB2). Each has been shown to profoundly inhibit angiogenesis in human tumors (18)(19)(20)(21)(22). Realtime (RT) QPCR and Western analysis showed that GRK3 is expressed at a higher level in metastatic cell lines than their poorly metastatic parental cell lines, and expression of TSP-1 and PAI-2 were down-regulated by GRK3 (Fig.…”

Section: Grk3 Suppresses Expression Of Antiangiogenesis Proteins Throm-mentioning

confidence: 99%

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GRK3 is essential for metastatic cells and promotes prostate tumor progression

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen against human kinases to identify those with previously undocumented roles in metastasis. We discovered that G-protein-coupled receptor kinase 3 (GRK3; or β-adrenergic receptor kinase 2) was not only necessary for survival and proliferation of metastatic cells, but also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 stimulated angiogenesis, at least in part through down-regulation of thrombospondin-1 and plasminogen activator inhibitor type 2. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastatic tumors. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis.functional screens | essential kinases | ADRBK2 | TSP-1 | PAI-2 M etastasis, and resultant organ failure, is responsible for more than 90% of cancer deaths (1). However, the biochemical and molecular mechanisms that regulate tumor progression to the metastatic phenotype are still poorly understood, especially the control of survival and proliferation of metastatic cells (2, 3). To form metastases, tumor cells need to complete a multistep process, including escape from primary tumor site, intravasation into circulation, and extravasation into secondary sites, where they must be able to survive and proliferate. Cells at these sites then progress from micrometastases to macrometastases through enhancement of angiogenesis and other processes (4, 5). Recent studies have suggested that cell migration and invasion can occur effectively during early phases of primary tumor development (6-8), and survival and proliferation of metastatic cells may be the rate-limiting step for what we often describe as metastasis (2, 3). As such, the ability to initiate angiogenesis at the metastatic site could serve as a distinguishing functional feature between metastatic and nonmetastatic cells.Our previous work has shown the value of comparing functional differences between closely related cell lines through RNAi screens (9-12). In this study, we performed RNAi screens to compare essential kinase profiles between paired highly metastatic and weakly metastatic human cancer cell lines, and identified kinases that are essential preferentially for highly metastatic cells. To prioritize these kinases for further studies, an orthotopic prostate metastasis model was then used to test the corresponding cDNAs in poorly metastatic cells. From these studies, we discovered that G-protein-coupled receptor kinase 3 (GRK3) is not only essential for survival and proliferation of metastatic cells in vitro and in vivo, but also is capable of promoting primary tumor growth ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Grk3 Suppresses Expression Of Antiangiogenesis Proteins Throm-mentioning

confidence: 99%

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GRK3 is essential for metastatic cells and promotes prostate tumor progression

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…103 Preclinical and translational advances. Within the abundant preclinical literature that has been published during the last 13 months on ICD-inducing chemotherapeutics, we found of particular interest the works of: (1) Pallasch and colleagues (Massachusetts Institute of Technology; Cambridge, MA, US), who demonstrated that cyclophosphamide induces an acute secretory phenotype in malignant cells, stimulating the release of various immunostimulatory cytokines that promotes a macrophagedriven, tumor-targeting innate immune response; [104][105][106] (2) Tavora and collaborators (Barts Cancer Institute; London, UK), who showed that the inhibition of protein tyrosine kinase 2 (PTK2, also known as FAK) [107][108][109] in the endothelial tumor [130][131][132][133] in the establishment of a collagenenriched tumor microenvironment contributing to the resistance of (at least a subset of) breast carcinomas to doxorubicin. 134 Recently initiated clinical trials.…”

Section: Update On the Development Of Icd-inducing Chemotherapeuticsmentioning

confidence: 99%

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

et al. 2015

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“…Consequently, uPA and SerpinE1 expression is recommended as an independent prognostic indicator in node-negative breast cancer (9). On the contrary, tumor expression of SerpinB2 is correlated with increased relapse-free survival in breast cancer (and possibly other cancer types) (10). Further, the relationship between outcome and high SerpinB2 levels in node-negative breast cancer is only relevant if uPA levels are also elevated (1,11), suggesting that the inhibitory relationship between uPA and SerpinB2 mediates this functionality.…”

mentioning

confidence: 99%

Dependence on Endocytic Receptor Binding via a Minimal Binding Motif Underlies the Differential Prognostic Profiles of SerpinE1 and SerpinB2 in Cancer

Cochran

Croucher

Lobov

et al. 2011

Journal of Biological Chemistry

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Tumor overexpression of urokinase-type plasminogen activator (uPA) and its specific inhibitor SerpinE1 (plasminogen activator inhibitor type-1) correlates with poor prognosis and increased metastatic potential. Conversely, tumor expression of uPA and another specific inhibitor, SerpinB2 (plasminogen activator inhibitor type-2), are associated with favorable outcome and relapse-free survival. It is not known how overexpression of these uPA inhibitors results in such disparate outcomes. A possible explanation may be related to the presence of a proposed low density lipoprotein receptor (LDLR)-binding motif in SerpinE1 responsible for mitogenic signaling via ERK that is absent in SerpinB2. We now show that complementation of such a LDLR-binding motif in SerpinB2 by mutagenesis of two key residues enabled high affinity binding to very LDLR (VLDLR). Furthermore, the VLDLR-binding SerpinB2 form behaved in a manner indistinguishable from SerpinE1 in terms of enhanced uPA-SerpinB2 complex endocytosis and subsequent ERK phosphorylation and cell proliferation; that is, the introduction of the LDLR-binding motif to SerpinB2 was necessary and sufficient to allow it to acquire characteristics of SerpinE1 associated with malignancy. In conclusion, this study defines the structural elements underlying the distinct interactions of SerpinE1 versus SerpinB2 with endocytic receptors and how differential VLDLR binding impacts on downstream cellular behavior. This has clear relevance to understanding the paradoxical disease outcomes associated with overexpression of these serpins in cancer.SerpinE1 (plasminogen activator inhibitor type-1, PAI-1) 4 and SerpinB2 (plasminogen activator inhibitor type-2, PAI-2) are both efficient inhibitors of the urokinase-type plasminogen activator (uPA), a key enzyme in the tissue remodeling process. Combined tumor overexpression of uPA, its receptor (uPAR), and SerpinE1 (serine protease inhibitor E1) is strongly correlated with poor patient prognosis (1-3) and metastatic potential (4 -8). Consequently, uPA and SerpinE1 expression is recommended as an independent prognostic indicator in node-negative breast cancer (9). On the contrary, tumor expression of SerpinB2 is correlated with increased relapse-free survival in breast cancer (and possibly other cancer types) (10). Further, the relationship between outcome and high SerpinB2 levels in node-negative breast cancer is only relevant if uPA levels are also elevated (1, 11), suggesting that the inhibitory relationship between uPA and SerpinB2 mediates this functionality.Binding of uPA to uPAR has been reported to induce the activation of numerous cell type-specific signaling pathways, such as MAPK/ERK, JAK/STAT, Src, focal adhesion kinase, and Rac, thereby affecting cell adhesion, migration, differentiation, and apoptosis (12). Because uPAR is not a transmembrane protein, being linked to the cell surface by a glycosylphosphatidylinositol anchor, uPA/uPAR signaling is mediated by integrins and several other adaptor molecules, including members of the lo...

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Revisiting the biological roles of PAI2 (SERPINB2) in cancer

Cited by 178 publications

References 150 publications

GRK3 is essential for metastatic cells and promotes prostate tumor progression

GRK3 is essential for metastatic cells and promotes prostate tumor progression

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

Dependence on Endocytic Receptor Binding via a Minimal Binding Motif Underlies the Differential Prognostic Profiles of SerpinE1 and SerpinB2 in Cancer

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