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ISSN Druckformat: 1040-8401
ISSN Online: 2162-6472
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The Ron Receptor Tyrosine Kinase: A Key Regulator of Inflammation and Cancer Progression
ABSTRAKT
Numerous studies have documented abnormal expression and activation of the Ron receptor tyrosine kinase in a variety of human malignancies. Here we review the literature regarding the molecular mechanisms governing Ron regulation, the biological functions of Ron, the effect of Ron on cancer development, and potential therapeutic implications. In epithelial cells, activation of Ron by its ligand, macrophage stimulating protein, mediates a number of biological events including cell growth, motility, and epithelial to mesenchymal transition. Overexpression and/or activation of Ron has been implicated in the progression and metastasis of diverse epithelial cancers, where it plays a causal role in tumor development by promoting growth, survival, and motility of tumor cells. As a crucial regulator of inflammation, Ron inhibits classic macrophage activation and promotes alternative activation of macrophages, resulting in the resolution of inflammation and tissue repair. In addition, Ron alleviates antitumor immunity by promoting the alternative activation of tumor-associated macrophages, and Ron expression in the tumor microenvironment promotes the outgrowth of metastatic colonies. Hence, Ron is a promising therapeutic target for the treatment of epithelial cancers.
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Witte Merlijn, Huitema Leonie F.A., Nieuwenhuis Edward E.S., Brugman Sylvia, Deficiency in Macrophage-Stimulating Protein Results in Spontaneous Intestinal Inflammation and Increased Susceptibility Toward Epithelial Damage in Zebrafish, Zebrafish, 11, 6, 2014. Crossref
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Walcott Brian P., Patel Anoop P., Stapleton Christopher J., Trivedi Rikin A., Young Adam M.H., Ogilvy Christopher S., Multiplexed protein profiling after aneurysmal subarachnoid hemorrhage: Characterization of differential expression patterns in cerebral vasospasm, Journal of Clinical Neuroscience, 21, 12, 2014. Crossref
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Raeppel Franck, Raeppel Stéphane L., Therrien Eric, Design, synthesis and RON receptor tyrosine kinase inhibitory activity of new head groups analogs of LCRF-0004, Bioorganic & Medicinal Chemistry Letters, 25, 18, 2015. Crossref
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Raeppel Stéphane L., Raeppel Franck, Therrien Eric, Design and synthesis of close analogs of LCRF-0004, a potent and selective RON receptor tyrosine kinase inhibitor, Bioorganic & Medicinal Chemistry Letters, 25, 12, 2015. Crossref
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Gross Stefan, Rahal Rami, Stransky Nicolas, Lengauer Christoph, Hoeflich Klaus P., Targeting cancer with kinase inhibitors, Journal of Clinical Investigation, 125, 5, 2015. Crossref
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Raeppel Stéphane L., Therrien Eric, Raeppel Franck, Design and synthesis of constrained analogs of LCRF-0004 as potent RON tyrosine kinase inhibitors, Bioorganic & Medicinal Chemistry Letters, 25, 17, 2015. Crossref
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Faham Najme, Welm Alana L., RON Signaling Is a Key Mediator of Tumor Progression in Many Human Cancers, Cold Spring Harbor Symposia on Quantitative Biology, 81, 2016. Crossref
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Guo Qianyu, Huang Fan, Goncalves Christophe, del Rincón Sonia V., Miller Wilson H., Translation of cancer immunotherapy from the bench to the bedside, in Immunotherapy of Cancer, 143, 2019. Crossref
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Chen Zhenghu, Zhao Yanling, Yu Yang, Pang Jonathan C., Woodfield Sarah E., Tao Ling, Guan Shan, Zhang Huiyuan, Bieerkehazhi Shayahati, Shi Yan, Patel Roma, Vasudevan Sanjeev A., Yi Joanna S., Muscal Jodi A., Xu Guo-Tong, Yang Jianhua, Small molecule inhibitor regorafenib inhibits RET signaling in neuroblastoma cells and effectively suppresses tumor growth in vivo, Oncotarget, 8, 61, 2017. Crossref
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Chen Shao-Long, Wang Guo-Ping, Shi Dan-Rong, Yao Shu-Hao, Chen Ke-Da, Yao Hang-Ping, RON in hepatobiliary and pancreatic cancers: Pathogenesis and potential therapeutic targets, World Journal of Gastroenterology, 27, 20, 2021. Crossref
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Chakedis J, French R, Babicky M, Jaquish D, Howard H, Mose E, Lam R, Holman P, Miyamoto J, Walterscheid Z, Lowy A M, A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells, Oncogene, 35, 25, 2016. Crossref
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Zarei Omid, Raeppel Stéphane L., Hamzeh-Mivehroud Maryam, An alignment-independent three-dimensional quantitative structure–activity relationship study on ron receptor tyrosine kinase inhibitors, Journal of Bioinformatics and Computational Biology, 20, 03, 2022. Crossref