Mechanism of suppressors of cytokine signaling 1 inhibition of epithelial-mesenchymal transition signaling through ROS regulation in colon cancer cells: suppression of Src leading to thioredoxin up-regulation.
Reactive oxygen species (ROS) participate in malignant progression of cancers including epithelial-mesenchymal transition (EMT). We have investigated the role of suppressors of cytokine signaling (SOCS)1 as an inhibitor of ROS-induced EMT using colon cancer cell lines transduced with SOCS1 and shSOCS1. Hydrogen peroxide treatment induced EMT features such as elevation of vimentin and Snail with a corresponding reduction of E-cadherin. The EMT markers are significantly decreased upon SOCS1 over-expression while increased under SOCS1 knock-down. SOCS1 inhibited ROS signaling pathways associated with EMT such as Src, Jak, and p65. Of note, strong up-regulation of Src activity in SOCS1-ablated cells was responsible for the elevated signaling leading to EMT, as shSrc or Src inhibitor abolished the shSOCS1-induced promotion of EMT response. Suppression of ROS-inducible EMT markers and invasion in SOCS1 over-expressing cells correlated with significantly low intracellular ROS levels in these cells. Analysis of antioxidant enzymes in SOCS1-transduced cells revealed a selective up-regulation of thioredoxin (Trx1), while thioredoxin ablation restored ROS levels and the associated EMT markers. As a mechanism of thioredoxin up-regulation by SOCS1, inhibition of Src activity promoting nuclear translocation of Nrf-2 is proposed. Taken together, our data strongly indicate that SOCS1 antagonizes EMT by suppressing Src activity, leading to thioredoxin expression and down-regulation of ROS levels in colon cancer cells.
Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 440-746, Korea.
Sung-Hoon
SH
Jung
Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 440-746, Korea.
Su-Min
SM
Kim
Department of Biological Science, College of Science, Sungkyunkwan University, Suwon 440-746, Korea.
Choong-Eun
CE
Lee
D021581:Active Transport, Cell Nucleus; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; C000604407:SNAI1 protein, human; C108944:SOCS1 protein, human; D000071250:Snail Family Transcription Factors; D000071222:Suppressor of Cytokine Signaling 1 Protein; C491203:TXN protein, human; D014746:Vimentin; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D019061:src-Family Kinases
EMT signaling; Src; reactive oxygen species; suppressors of cytokine signaling; thioredoxin