Suppression of Urokinase-Type Plasminogen Activator Receptor by Docosahexaenoic Acid Mediated by Heme Oxygenase-1 in 12--Tetradecanoylphorbol-13-Acetate-Induced Human Endothelial Cells

Overview

Journal Front Pharmacol

Date 2020 Dec 31

PMID 33381031

Citations 1

Authors

Sen Lian

Shinan Li

Dhiraj Kumar Sah

Nam Ho Kim

Vinoth-Kumar Lakshmanan

Young Do Jung

Affiliations

Soon will be listed here.

Abstract

Urokinase-type plasminogen activator receptor (uPAR) plays a crucial role in inflammation and tumor metastasis. Docosahexaenoic acid (DHA), a representative omega-3 polyunsaturated fatty acid, has been shown to exhibit anti-inflammatory and anti-tumor properties. However, the mechanism by which DHA negatively regulates uPAR expression is not yet understood. The aim of this study was to investigate the effect of DHA on 12--tetradecanoylphorbol-13-acetate (TPA)-induced uPAR expression and potential role of heme oxygenase-1 (HO-1) in DHA-induced inhibition of uPAR in human endothelial ECV304 cells. Results showed that TPA induced uPAR expression in a time dependent manner, while DHA inhibited uPAR expression in a concentration-dependent manner. Moreover, treatment with DHA induced HO-1 expression in a time- and concentration-dependent manner. In addition, DHA-induced inhibition of uPAR expression and cell invasion in TPA-stimulated cells was reversed by si-HO-1 RNA. Induction of HO-1 by ferric protoporphyrin IX (FePP) inhibited TPA-induced uPAR expression, and this effect was abolished by treatment with the HO-1 inhibitor tin protoporphyrin IX (SnPP). Additionally, carbon monoxide, an HO-1 product, attenuated TPA-induced uPAR expression and cell invasion. Collectively, these data suggest a novel role of DHA-induced HO-1 in reducing uPAR expression and cell invasion in human endothelial ECV304 cells.

Citing Articles

Urokinase-type plasminogen activator receptor (uPAR) as a therapeutic target in cancer.

Zhai B, Tian H, Sun J, Zou J, Zhang X, Cheng J J Transl Med. 2022; 20(1):135.

PMID: 35303878 PMC: 8932206. DOI: 10.1186/s12967-022-03329-3.

References

Chung H, Choi B, Kwon Y, Kim Y . Interactive relations between nitric oxide (NO) and carbon monoxide (CO): heme oxygenase-1/CO pathway is a key modulator in NO-mediated antiapoptosis and anti-inflammation. Methods Enzymol. 2008; 441:329-38. DOI: 10.1016/S0076-6879(08)01218-4. View

Gopalakrishna R, Jaken S . Protein kinase C signaling and oxidative stress. Free Radic Biol Med. 2000; 28(9):1349-61. DOI: 10.1016/s0891-5849(00)00221-5. View

Morse D, Pischke S, Zhou Z, Davis R, Flavell R, Loop T . Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J Biol Chem. 2003; 278(39):36993-8. DOI: 10.1074/jbc.M302942200. View

Lian S, Xia Y, Nguyen T, Ung T, Yoon H, Kim N . Docosahexaenoic Acid Inhibits Tumor Promoter-Induced Urokinase-Type Plasminogen Activator Receptor by Suppressing PKCδ- and MAPKs-Mediated Pathways in ECV304 Human Endothelial Cells. PLoS One. 2016; 11(9):e0163395. PMC: 5031411. DOI: 10.1371/journal.pone.0163395. View

Merendino N, Costantini L, Manzi L, Molinari R, DEliseo D, Velotti F . Dietary ω -3 polyunsaturated fatty acid DHA: a potential adjuvant in the treatment of cancer. Biomed Res Int. 2013; 2013:310186. PMC: 3676987. DOI: 10.1155/2013/310186. View

Kobayashi H, Takeno M, Saito T, Takeda Y, Kirino Y, Noyori K . Regulatory role of heme oxygenase 1 in inflammation of rheumatoid arthritis. Arthritis Rheum. 2006; 54(4):1132-42. DOI: 10.1002/art.21754. View

von Schacky C . n-3 PUFA in CVD: influence of cytokine polymorphism. Proc Nutr Soc. 2007; 66(2):166-70. DOI: 10.1017/S0029665107005411. View

Becker J, Fukui H, Imai Y, Sekikawa A, Kimura T, Yamagishi H . Colonic expression of heme oxygenase-1 is associated with a better long-term survival in patients with colorectal cancer. Scand J Gastroenterol. 2007; 42(7):852-8. DOI: 10.1080/00365520701192383. View

Nguyen L, Ma D, Shui G, Wong P, Cazenave-Gassiot A, Zhang X . Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. 2014; 509(7501):503-6. DOI: 10.1038/nature13241. View

10.

Parfenova H, Leffler C, Basuroy S, Liu J, Fedinec A . Antioxidant roles of heme oxygenase, carbon monoxide, and bilirubin in cerebral circulation during seizures. J Cereb Blood Flow Metab. 2012; 32(6):1024-34. PMC: 3367218. DOI: 10.1038/jcbfm.2012.13. View

11.

Wagener F, van Beurden H, Von den Hoff J, Adema G, Figdor C . The heme-heme oxygenase system: a molecular switch in wound healing. Blood. 2003; 102(2):521-8. DOI: 10.1182/blood-2002-07-2248. View

12.

Lin H, Shen S, Lin C, Yang L, Chen Y . Baicalein inhibition of hydrogen peroxide-induced apoptosis via ROS-dependent heme oxygenase 1 gene expression. Biochim Biophys Acta. 2007; 1773(7):1073-86. DOI: 10.1016/j.bbamcr.2007.04.008. View

13.

Lagente V, Planquois J, Leclerc O, Schmidlin F, Bertrand C . Oxidative stress is an important component of airway inflammation in mice exposed to cigarette smoke or lipopolysaccharide. Clin Exp Pharmacol Physiol. 2008; 35(5-6):601-5. DOI: 10.1111/j.1440-1681.2007.04848.x. View

14.

Mignatti P, Rifkin D . Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein. 1996; 49(1-3):117-37. DOI: 10.1159/000468621. View

15.

Megias J, Busserolles J, Alcaraz M . The carbon monoxide-releasing molecule CORM-2 inhibits the inflammatory response induced by cytokines in Caco-2 cells. Br J Pharmacol. 2007; 150(8):977-86. PMC: 2013913. DOI: 10.1038/sj.bjp.0707184. View

16.

Wood K, DE Wet J, Dewji N, DeLuca M . Synthesis of active firefly luciferase by in vitro translation of RNA obtained from adult lanterns. Biochem Biophys Res Commun. 1984; 124(2):592-6. DOI: 10.1016/0006-291x(84)91595-x. View

17.

Hill M, Pereira V, Chauveau C, Zagani R, Remy S, Tesson L . Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase. FASEB J. 2005; 19(14):1957-68. DOI: 10.1096/fj.05-3875com. View

18.

Otterbein L, Choi A . Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol. 2000; 279(6):L1029-37. DOI: 10.1152/ajplung.2000.279.6.L1029. View

19.

Schiller H, Szekeres A, Binder B, Stockinger H, Leksa V . Mannose 6-phosphate/insulin-like growth factor 2 receptor limits cell invasion by controlling alphaVbeta3 integrin expression and proteolytic processing of urokinase-type plasminogen activator receptor. Mol Biol Cell. 2008; 20(3):745-56. PMC: 2633380. DOI: 10.1091/mbc.e08-06-0569. View

20.

Sawle P, Foresti R, Mann B, Johnson T, Green C, Motterlini R . Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. Br J Pharmacol. 2005; 145(6):800-10. PMC: 1576195. DOI: 10.1038/sj.bjp.0706241. View