The molecular effect of metastasis suppressors on Src signaling and tumorigenesis: new therapeutic targets
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Wensheng Liu2, Zaklina Kovacevic1, Zhihai Peng2, Runsen Jin4, Puxiongzhi Wang3, Fei Yue3, Minhua Zheng3, Michael L-H. Huang1, Patric J. Jansson1, Vera Richardson1, Danuta S. Kalinowski1, Darius J.R. Lane1, Angelica M. Merlot1, Sumit Sahni1 and Des R. Richardson1
1 Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia
2 Department of General Surgery, Shanghai Jiaotong University Affiliated First People’s Hospital, Shanghai, Peoples Republic of China
3 Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Peoples Republic of China
4 Department of Thoracic surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Peoples Republic of China
Des R. Richardson, email:
Zaklina Kovacevic, email:
Keywords: metastasis suppressor, Src, NDRG1, metastasis
Received: June 15, 2015 Accepted: August 15, 2015 Published: September 27, 2015
A major problem for cancer patients is the metastasis of cancer cells from the primary tumor. This involves: (1) migration through the basement membrane; (2) dissemination via the circulatory system; and (3) invasion into a secondary site. Metastasis suppressors, by definition, inhibit metastasis at any step of the metastatic cascade. Notably, Src is a non-receptor, cytoplasmic, tyrosine kinase, which becomes aberrantly activated in many cancer-types following stimulation of plasma membrane receptors (e.g., receptor tyrosine kinases and integrins). There is evidence of a prominent role of Src in tumor progression-related events such as the epithelial–mesenchymal transition (EMT) and the development of metastasis. However, the precise molecular interactions of Src with metastasis suppressors remain unclear. Herein, we review known metastasis suppressors and summarize recent advances in understanding the mechanisms of how these proteins inhibit metastasis through modulation of Src. Particular emphasis is bestowed on the potent metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1) and its interactions with the Src signaling cascade. Recent studies demonstrated a novel mechanism through which NDRG1 plays a significant role in regulating cancer cell migration by inhibiting Src activity. Moreover, we discuss the rationale for targeting metastasis suppressor genes as a sound therapeutic modality, and we review several examples from the literature where such strategies show promise. Collectively, this review summarizes the essential interactions of metastasis suppressors with Src and their effects on progression of cancer metastasis. Moreover, interesting unresolved issues regarding these proteins as well as their potential as therapeutic targets are also discussed.
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