Research Papers:

The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1

Wensheng Liu _, Fei Yue, Minhua Zheng, Angelica Merlot, Dong-Hun Bae, Michael Haung, Darius Lane, Patric Jansson, Goldie Yuan Lam Lui, Vera Richardson, Sumit Sahni, Danuta Kalinowski, Zaklina Kovacevic and Des. R. Richardson

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Oncotarget. 2015; 6:8851-8874. https://doi.org/10.18632/oncotarget.3316

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Wensheng Liu1,2, Fei Yue1, Minhua Zheng1, Angelica Merlot2, Dong-Hun Bae2, Michael Huang2, Darius Lane2, Patric Jansson2, Goldie Yuan Lam Liu2, Vera Richardson2, Sumit Sahni2, Danuta Kalinowski2, Zaklina Kovacevic2, Des. R. Richardson2

1Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China

2Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, Sydney, New South Wales 2006, Australia

Correspondence to:

Des R. Richardson, e-mail: [email protected]

Zaklina Kovacevic, e-mail: [email protected]

Minhua Zheng, e-mail: [email protected]

Keywords: NDRG1, metastasis suppressor, c-Src, cell migration

Received: December 20, 2014     Accepted: February 08, 2015     Published: April 10, 2015


N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that plays a key role in regulating signaling pathways involved in mediating cancer cell invasion and migration, including those derived from prostate, colon, etc. However, the mechanisms and molecular targets through which NDRG1 reduces cancer cell invasion and migration, leading to inhibition of cancer metastasis, are not fully elucidated. In this investigation, using NDRG1 over-expression models in three tumor cell-types (namely, DU145, PC3MM and HT29) and also NDRG1 silencing in DU145 and HT29 cells, we reveal that NDRG1 decreases phosphorylation of a key proto-oncogene, cellular Src (c-Src), at a well-characterized activating site (Tyr416). NDRG1-mediated down-regulation of EGFR expression and activation were responsible for the decreased phosphorylation of c-Src (Tyr416). Indeed, NDRG1 prevented recruitment of c-Src to EGFR and c-Src activation. Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a “molecular switch” to activate Rac1. NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, c-Abl, which then inhibited CrkII phosphorylation. Silencing NDRG1 increased cell migration relative to the control and inhibition of c-Src signaling using siRNA, or a pharmacological inhibitor (SU6656), prevented this increase. Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation. In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation. This study leads to important insights into the mechanism involved in inhibiting metastasis by NDRG1 and how to target these pathways with novel therapeutics.

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