Redrawing Urokinase Receptor (uPAR) Signaling with Cancer Driver Genes for Exploring Possible Anti-Cancer Targets and Drugs

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2023 Oct 28

PMID 37895906

Authors

Yu-Ching Chang

Chung-Ze Wu

Chao-Wen Cheng

Jin-Shuen Chen

Li-Chien Chang

Affiliations

Soon will be listed here.

Abstract

During tumorigenesis, urokinase (uPA) and uPA receptor (uPAR) play essential roles in mediating pathological progression in many cancers. To understand the crosstalk between the uPA/uPAR signaling and cancer, as well as to decipher their cellular pathways, we proposed to use cancer driver genes to map out the uPAR signaling. In the study, an integrated pharmaceutical bioinformatics approach that combined modulator identification, driver gene ontology networking, protein targets prediction and networking, pathway analysis and uPAR modulator screening platform construction was employed to uncover druggable targets in uPAR signaling for developing a novel anti-cancer modality. Through these works, we found that uPAR signaling interacted with 10 of 21 KEGG cancer pathways, indicating the important role of uPAR in mediating intracellular cancerous signaling. Furthermore, we verified that receptor tyrosine kinases (RTKs) and ribosomal S6 kinases (RSKs) could serve as signal hubs to relay uPAR-mediated cellular functions on cancer hallmarks such as angiogenesis, proliferation, migration and metastasis. Moreover, we established an in silico virtual screening platform and a uPAR-driver gene pair rule for identifying potential uPAR modulators to combat cancer. Altogether, our results not only elucidated the complex networking between uPAR modulation and cancer but also provided a paved way for developing new chemical entities and/or re-positioning clinically used drugs against cancer.

References

Rao P, Rao U . Statins decrease the expression of c-Myc protein in cancer cell lines. Mol Cell Biochem. 2020; 476(2):743-755. DOI: 10.1007/s11010-020-03940-2. View

Paul M, Mukhopadhyay A . Tyrosine kinase - Role and significance in Cancer. Int J Med Sci. 2005; 1(2):101-115. PMC: 1074718. DOI: 10.7150/ijms.1.101. View

Fruman D, Snapper S, Yballe C, Davidson L, Yu J, Alt F . Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Science. 1999; 283(5400):393-7. DOI: 10.1126/science.283.5400.393. View

Subramanian A, Narayan R, Corsello S, Peck D, Natoli T, Lu X . A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell. 2017; 171(6):1437-1452.e17. PMC: 5990023. DOI: 10.1016/j.cell.2017.10.049. View

Koshelnick Y, Ehart M, Hufnagl P, Heinrich P, Binder B . Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598. J Biol Chem. 1997; 272(45):28563-7. DOI: 10.1074/jbc.272.45.28563. View

Dennler S, Itoh S, Vivien D, Ten Dijke P, Huet S, Gauthier J . Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J. 1998; 17(11):3091-100. PMC: 1170648. DOI: 10.1093/emboj/17.11.3091. View

Gupta R, Chetty C, Bhoopathi P, Lakka S, Mohanam S, Rao J . Downregulation of uPA/uPAR inhibits intermittent hypoxia-induced epithelial-mesenchymal transition (EMT) in DAOY and D283 medulloblastoma cells. Int J Oncol. 2010; 38(3):733-44. DOI: 10.3892/ijo.2010.883. View

Taniguchi C, Winnay J, Kondo T, Bronson R, Guimaraes A, Aleman J . The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling. Cancer Res. 2010; 70(13):5305-15. PMC: 3204358. DOI: 10.1158/0008-5472.CAN-09-3399. View

Blasi F, Carmeliet P . uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol. 2002; 3(12):932-43. DOI: 10.1038/nrm977. View

10.

Laurenzana A, Chilla A, Luciani C, Peppicelli S, Biagioni A, Bianchini F . uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells. Int J Cancer. 2017; 141(6):1190-1200. DOI: 10.1002/ijc.30817. View

11.

Blasi F . Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-u-PAR-PAI-1 system. Thromb Haemost. 1999; 82(2):298-304. View

12.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S . PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 2018; 47(D1):D1102-D1109. PMC: 6324075. DOI: 10.1093/nar/gky1033. View

13.

Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D . RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011; 11(11):761-74. PMC: 3632399. DOI: 10.1038/nrc3106. View

14.

Biagioni A, Chilla A, Del Rosso M, Fibbi G, Scavone F, Andreucci E . CRISPR/Cas9 uPAR Gene Knockout Results in Tumor Growth Inhibition, EGFR Downregulation and Induction of Stemness Markers in Melanoma and Colon Carcinoma Cell Lines. Front Oncol. 2021; 11:663225. PMC: 8163229. DOI: 10.3389/fonc.2021.663225. View

15.

Obrador E, Salvador-Palmer R, Jihad-Jebbar A, Lopez-Blanch R, Dellinger T, Dellinger R . Pterostilbene in Cancer Therapy. Antioxidants (Basel). 2021; 10(3). PMC: 8004113. DOI: 10.3390/antiox10030492. View

16.

Houles T, Roux P . Defining the role of the RSK isoforms in cancer. Semin Cancer Biol. 2017; 48:53-61. DOI: 10.1016/j.semcancer.2017.04.016. View

17.

Di Mauro C, Pesapane A, Formisano L, Rosa R, Damato V, Ciciola P . Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors. Sci Rep. 2017; 7(1):9388. PMC: 5571185. DOI: 10.1038/s41598-017-10062-1. View

18.

Hirsh V . Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on Afatinib. BioDrugs. 2015; 29(3):167-83. PMC: 4488453. DOI: 10.1007/s40259-015-0130-9. View

19.

Chin C, Chen S, Wu H, Ho C, Ko M, Lin C . cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014; 8 Suppl 4:S11. PMC: 4290687. DOI: 10.1186/1752-0509-8-S4-S11. View

20.

Yuan C, Guo Z, Yu S, Jiang L, Huang M . Development of inhibitors for uPAR: blocking the interaction of uPAR with its partners. Drug Discov Today. 2021; 26(4):1076-1085. DOI: 10.1016/j.drudis.2021.01.016. View