Abstract
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.
Highlights
Reactive oxygen species (ROS) have been implicated during initiation, promotion, and malignant progression for cancers of the breast, liver, and colon [1,2,3]
Since ROS signaling is important in the induction of the malignant growth of tumors through epithelial - mesenchyme transition (EMT), the ROS inhibiting action of SOCS1 to suppress EMT has been a subject of interest
Since cells transduced with SOCS1 exhibited reduced expression of EMT markers resembling the effect of anti-oxidant, we have examined the effect of SOCS1 or shSOCS1 on the intracellular ROS levels
Summary
Reactive oxygen species (ROS) have been implicated during initiation, promotion, and malignant progression for cancers of the breast, liver, and colon [1,2,3]. EMT causes epithelial cells to lose their polarity and intercellular adhesion, and to gain fibroblast-like and invasive properties to become cells with mesenchymal features [6, 7]. It has been reported that cancer cells under hypoxia exhibited increased intracellular ROS levels and progressed to EMT, the process of which was blocked by an anti-oxidant N-acetyl cysteine (NAC) [12]. Both MMP3 and MMP9 are implicated as inducers of ROS leading to EMT in breast and colon cancer cells [13, 14]. While these findings provide insights for the mechanism of ROS generation and ROS-induced EMT process in diverse tumor cells, strategies targeting ROS signal pathways to prevent EMT have not been extensively investigated
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