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7. PAR2 controls cholesterol homeostasis and lipid metabolism in nonalcoholic fatty liver disease

Author

Rajashree Rana, Andrew M. Shearer, Elizabeth K. Fletcher, Nga Nguyen, Srijoy Guha, Daniel H. Cox, Manal Abdelmalek, Ying Wang, James D. Baleja, Lidija Covic, and Athan Kuliopulos

Subjects
Internal medicine, RC31-1245
Abstract

Objective: Increases in hepatic and plasma cholesterol occur in patients with nonalcoholic fatty liver disease (NAFLD), although the reason for this is not well understood. We investigated whether Protease-Activated Receptor 2 (PAR2) plays a role in cholesterol and lipid homeostasis in NAFLD. Methods: Human liver biopsies (n = 108) were quantified for PAR2 expression from NAFLD cases randomly selected and stratified by liver fibrosis stage, the primary predictor for clinical outcomes, while controlling for age, gender, and BMI between fibrosis groups. Demographic data and laboratory studies on plasma samples were obtained within 6 months of liver biopsy. Wild-type and PAR2-KO (C57BL/6 F2rl1−/−) mice were fed either normal or high fat diet for 16 weeks and plasma and liver assayed for lipids and soluble metabolites. Results: Severity of NAFLD and plasma cholesterol levels significantly correlated with hepatocyte PAR2 expression in NAFLD patients. Conversely, PAR2 deficiency in mice resulted in reduced expression of key hepatic genes involved in cholesterol synthesis, a 50% drop in plasma and total liver cholesterol, and induced a reverse cholesterol transport system that culminated in 25% higher fecal bile acid output. PAR2-deficient mice exhibited enhanced fatty acid β-oxidation with a ketogenic shift and an unexpected increase in liver glycogenesis. Mechanistic studies identified Gi-Jnk1/2 as key downstream effectors of protease-activated PAR2 in the regulation of lipid and cholesterol homeostasis in liver. Conclusions: These data indicate that PAR2 may be a new target for the suppression of plasma cholesterol and hepatic fat accumulation in NAFLD and related metabolic conditions. Keywords: Cholesterol, Energy metabolism, Fatty liver, Protease-activated receptor 2, NASH

Published
2019
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9. Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia.

Author

O'Callaghan, Katie, Lee, Lydia, Nguyen, Nga, Hsieh, Mo-Ying, Kaneider, Nicole C, Klein, Andreas K, Sprague, Kellie, Van Etten, Richard A, Kuliopulos, Athan, and Covic, Lidija

Subjects
Amino Acid Sequence, Animals, Antineoplastic Agents: administration & dosage, chemistry, Drug Delivery Systems, Female, Humans, Interleukin Receptor Common gamma Subunit: genetics, Leukemia, Lymphoid: drug therapy, metabolism, pathology, Lipopeptides: administration & dosage, chemical synthesis, chemistry, therapeutic use, Lymphoma: drug therapy, metabolism, pathology, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Models, Molecular, Molecular Targeted Therapy, Receptors, CXCR4: antagonists & inhibitors, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
Abstract

The chemokine receptor CXCR4, which normally regulates stromal stem cell interactions in the bone marrow, is highly expressed on a variety of malignant hematologic cells, including lymphoma and lymphocytic leukemias. A new treatment concept has arisen wherein CXCR4 may be an effective therapeutic target as an adjunct to treatment of hematologic neoplasms with chemo- and immunotherapy. In the present study, we developed pepducins, cell-penetrating lipopeptide antagonists of CXCR4, to interdict CXCL12-CXCR4 transmembrane signaling to intracellular G-proteins. We demonstrate that pepducins targeting the first (i1) or third (i3) intracellular loops of CXCR4 completely abrogate CXCL12-mediated cell migration of lymphocytic leukemias and lymphomas. Stromal-cell coculture protects lymphoma cells from apoptosis in response to treatment with the CD20-targeted Ab rituximab. However, combination treatment with CXCR4 pepducins and rituximab significantly increases the apoptotic effect of rituximab. Furthermore, treatment of mice bearing disseminated lymphoma xenografts with pepducins alone or in combination with rituximab significantly increased their survival. These data demonstrate that CXCL12-CXCR4 signaling can be effectively inhibited by cell-penetrating pepducins, which represents a potential new treatment strategy for lymphoid malignancies.

Published
2012

34. Supplementary Table S2 from Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer

Author

Athan Kuliopulos, Sheida Sharifi, Gissou Azabdaftari, Katherine Lazarides, Nicole C. Kaneider, Leila M. Sevigny, Lidija Covic, and Anika Agarwal

Abstract

Supplementary Table S2 from Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer

Published
2023

35. Supplementary Fig. S4 from Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer

Author

Athan Kuliopulos, Sheida Sharifi, Gissou Azabdaftari, Katherine Lazarides, Nicole C. Kaneider, Leila M. Sevigny, Lidija Covic, and Anika Agarwal

Abstract

Supplementary Fig. S4 from Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer

Published
2023

36. Data from Targeting a metalloprotease-PAR1 signaling system with cell-penetrating pepducins inhibits angiogenesis, ascites, and progression of ovarian cancer

Author

Athan Kuliopulos, Sheida Sharifi, Gissou Azabdaftari, Katherine Lazarides, Nicole C. Kaneider, Leila M. Sevigny, Lidija Covic, and Anika Agarwal

Abstract

Gene chip and proteomic analyses of tumors and stromal tissue has led to the identification of dozens of candidate tumor and host components potentially involved in tumor-stromal interactions, angiogenesis, and progression of invasive disease. In particular, matrix metalloproteases (MMP) have emerged as important biomarkers and prognostic factors for invasive and metastatic cancers. From an initial screen of benign versus malignant patient fluids, we delineated a metalloprotease cascade comprising MMP-14, MMP-9, and MMP-1 that culminates in activation of PAR1, a G protein-coupled protease-activated receptor up-regulated in diverse cancers. In xenograft models of advanced peritoneal ovarian cancer, PAR1-dependent angiogenesis, ascites formation, and metastasis were effectively inhibited by i.p. administration of cell-penetrating pepducins based on the intracellular loops of PAR1. These data provide an in vivo proof-of-concept that targeting the metalloprotease-PAR1 signaling system may be a novel therapeutic approach in the treatment of ovarian cancer. [Mol Cancer Ther 2008;7(9):2746–57]

Published
2023

39. Supplementary Figure 3 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Author

Lidija Covic, Athan Kuliopulos, Powen Tu, Katie O'Callaghan, Nga Nguyen, Anika Agarwal, Adrienne Boire, and Eric Yang

Abstract

Supplementary Figure 3 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Published
2023

42. Data from Identification of a Metalloprotease-Chemokine Signaling System in the Ovarian Cancer Microenvironment: Implications for Antiangiogenic Therapy

Author

Athan Kuliopulos, Lidija Covic, Francis H. Lam, Marianthi Balla, Rajani Kaimal, Sarah L. Tressel, and Anika Agarwal

Abstract

Ovarian cancer is a lethal gynecologic malignancy that may benefit from new therapies that block key paracrine pathways involved in tumor-stromal interactions and tumor vascularity. It was recently shown that matrix metalloprotease-1 (MMP1) activation of the G protein–coupled receptor protease-activated receptor-1 (PAR1) is an important stimulator of angiogenesis and metastasis in peritoneal mouse models of ovarian cancer. In the present study, we tested the hypothesis that MMP1-PAR1 promotes angiogenesis through its paracrine control of angiogenic chemokine receptors. We found that MMP1-PAR1 activation induces the secretion of several angiogenic factors from ovarian carcinoma cells, most prominently interleukin (IL)-8, growth-regulated oncogene-α (GRO-α), and monocyte chemoattractant protein-1. The secreted IL-8 and GRO-α acts on endothelial CXCR1/2 receptors in a paracrine manner to cause robust endothelial cell proliferation, tube formation, and migration. A cell-penetrating pepducin, X1/2pal-i3, which targets the conserved third intracellular loop of both CXCR1 and CXCR2 receptors, significantly inhibited endothelial cell proliferation, tube formation, angiogenesis, and ovarian tumor growth in mice. Matrigel plugs mixed with MMP1-stimulated, OVCAR-4–conditioned media showed a dramatic 33-fold increase in blood vessel formation in mice. The X1/2pal-i3 pepducin completely inhibited MMP1-dependent angiogenesis compared with a negative control pepducin or vehicle. Conversely, a vascular endothelial growth factor–directed antibody, Avastin, suppressed angiogenesis in mice but, as expected, was unable to inhibit IL-8 and GRO-α–dependent endothelial tube formation in vitro. These studies identify a critical MMP1-PAR1-CXCR1/2 paracrine pathway that might be therapeutically targeted for ovarian cancer treatment. Cancer Res; 70(14); 5880–90. ©2010 AACR.

Published
2023

43. Supplementary Figure 5 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Author

Lidija Covic, Athan Kuliopulos, Powen Tu, Katie O'Callaghan, Nga Nguyen, Anika Agarwal, Adrienne Boire, and Eric Yang

Abstract

Supplementary Figure 5 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Published
2023

45. Supplementary Figure 7 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Author

Lidija Covic, Athan Kuliopulos, Powen Tu, Katie O'Callaghan, Nga Nguyen, Anika Agarwal, Adrienne Boire, and Eric Yang

Abstract

Supplementary Figure 7 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Published
2023

46. Data from Tumor-Derived Cyr61(CCN1) Promotes Stromal Matrix Metalloproteinase-1 Production and Protease-Activated Receptor 1–Dependent Migration of Breast Cancer Cells

Author

Lidija Covic, Roger A. Graham, Athan Kuliopulos, and Nga Nguyen

Abstract

Matrix metalloproteinases (MMPs) play a central role in remodeling the tumor-stromal microenvironment. We recently determined that stromal-derived MMP-1 also acts as a signaling molecule by cleaving protease-activated receptor 1 (PAR1) to cause breast cancer cell migration and invasion. Here, we show that ectopic PAR1 expression induces expression of the angiogenic factor Cyr61(CCN1) in breast cancer cells. The tumor-derived Cyr61 acts as an invasogenic signaling molecule that induces MMP-1 expression in adjacent stromal fibroblasts. Gene silencing of Cyr61 in breast cancer cells suppresses MMP-1 induction in stromal fibroblasts resulting in a major loss in migration of the cancer cells toward the fibroblasts. Cyr61-dependent loss of migration was complemented by exogenous MMP-1 and required the presence of the functional PAR1 receptor on the breast cancer cells. These results suggest that interrupting tumor-stromal cell communication by targeting Cyr61 may provide an alternative therapeutic approach for the treatment of invasive breast cancer. (Cancer Res 2006; 66(5): 2658-65)

Published
2023

47. Supplementary Figure 6 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Author

Lidija Covic, Athan Kuliopulos, Powen Tu, Katie O'Callaghan, Nga Nguyen, Anika Agarwal, Adrienne Boire, and Eric Yang

Abstract

Supplementary Figure 6 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Published
2023

48. Supplementary Figure 2 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Author

Lidija Covic, Athan Kuliopulos, Powen Tu, Katie O'Callaghan, Nga Nguyen, Anika Agarwal, Adrienne Boire, and Eric Yang

Abstract

Supplementary Figure 2 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Published
2023

49. Supplementary Figure 4 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Author

Lidija Covic, Athan Kuliopulos, Powen Tu, Katie O'Callaghan, Nga Nguyen, Anika Agarwal, Adrienne Boire, and Eric Yang

Abstract

Supplementary Figure 4 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Published
2023

50. Supplementary Figure Legends 1-7 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Author

Lidija Covic, Athan Kuliopulos, Powen Tu, Katie O'Callaghan, Nga Nguyen, Anika Agarwal, Adrienne Boire, and Eric Yang

Abstract

Supplementary Figure Legends 1-7 from Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Published
2023

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