title: The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.
abstract: 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.
authors: Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China.|Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Wensheng
authors: W
authors: Liu
authors: Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China.
authors: Fei
authors: F
authors: Yue
authors: Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China.
authors: Minhua
authors: M
authors: Zheng
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Angelica
authors: A
authors: Merlot
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Dong-Hun
authors: DH
authors: Bae
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Michael
authors: M
authors: Huang
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Darius
authors: D
authors: Lane
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Patric
authors: P
authors: Jansson
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Goldie Yuan Lam
authors: GY
authors: Lui
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Vera
authors: V
authors: Richardson
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Sumit
authors: S
authors: Sahni
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Danuta
authors: D
authors: Kalinowski
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Zaklina
authors: Z
authors: Kovacevic
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Des R
authors: DR
authors: Richardson
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000473:pathology; D050719:Crk-Associated Substrate Protein / Q000502:physiology; D015536:Down-Regulation; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016391:Genes, src; D006801:Humans; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D009363:Neoplasm Proteins / Q000502:physiology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology; D011499:Protein Processing, Post-Translational; D000090063:Proto-Oncogene Mas; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology; D050737:Proto-Oncogene Proteins c-crk / Q000502:physiology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013449:Sulfonamides; D054462:p21-Activated Kinases / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000502:physiology; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D050719:Crk-Associated Substrate Protein; D066246:ErbB Receptors; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D016315:Proto-Oncogene Proteins c-abl; D050737:Proto-Oncogene Proteins c-crk; D016392:Proto-Oncogene Proteins pp60(c-src); D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D013449:Sulfonamides; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C493841:BCAR1 protein, human; C000715470:MAS1 protein, human; C107953:RAC1 protein, human; C416927:SU 6656; C512478:EGFR protein, human; C515903:PAK1 protein, human
keywords: NDRG1; c-Src; cell migration; metastasis suppressor