SOCS1 counteracts ROS-mediated survival signals and promotes apoptosis by modulating cell cycle to increase radiosensitivity of colorectal cancer cells
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As negative regulators of cytokine signaling pathways, suppressorsof cytokine signaling (SOCS) proteins have been reportedto possess both pro-tumor and anti-tumor functions. Our recentstudies have demonstrated suppressive effects of SOCS1 onepithelial to mesenchymal signaling in colorectal cancer cellsin response to fractionated ionizing radiation or oxidative stress. The objective of the present study was to determine the radiosensitizingaction of SOCS1 as an anti-tumor mechanism in colorectalcancer cell model. In HCT116 cells exposed to ionizingradiation, SOCS1 over-expression shifted cell cycle arrest fromG2/M to G1 and promoted radiation-induced apoptosis in ap53-dependent manner with down-regulation of cyclin B andup-regulation of p21. On the other hand, SOCS1 knock-downresulted in a reduced apoptosis with a decrease in G1 arrest. The regulatory action of SOCS1 on the radiation response wasmediated by inhibition of radiation-induced Jak3/STAT3 andErk activities, thereby blocking G1 to S transition. Radiation-inducedearly ROS signal was responsible for the activation ofJak3/Erk/STAT3 that led to cell survival response. Our data collectivelyindicate that SOCS1 can promote radiosensitivity ofcolorectal cancer cells by counteracting ROS-mediated survivalsignal, thereby blocking cell cycle progression from G1 to S. The resulting increase in G1 arrest with p53 activation then contributesto the promotion of apoptotic response upon radiation. Thus, induction of SOCS1 expression may increase therapeuticefficacy of radiation in tumors with low SOCS1 levels.
Abstract
As negative regulators of cytokine signaling pathways, suppressorsof cytokine signaling (SOCS) proteins have been reportedto possess both pro-tumor and anti-tumor functions. Our recentstudies have demonstrated suppressive effects of SOCS1 onepithelial to mesenchymal signaling in colorectal cancer cellsin response to fractionated ionizing radiation or oxidative stress. The objective of the present study was to determine the radiosensitizingaction of SOCS1 as an anti-tumor mechanism in colorectalcancer cell model. In HCT116 cells exposed to ionizingradiation, SOCS1 over-expression shifted cell cycle arrest fromG2/M to G1 and promoted radiation-induced apoptosis in ap53-dependent manner with down-regulation of cyclin B andup-regulation of p21. On the other hand, SOCS1 knock-downresulted in a reduced apoptosis with a decrease in G1 arrest. The regulatory action of SOCS1 on the radiation response wasmediated by inhibition of radiation-induced Jak3/STAT3 andErk activities, thereby blocking G1 to S transition. Radiation-inducedearly ROS signal was responsible for the activation ofJak3/Erk/STAT3 that led to cell survival response. Our data collectivelyindicate that SOCS1 can promote radiosensitivity ofcolorectal cancer cells by counteracting ROS-mediated survivalsignal, thereby blocking cell cycle progression from G1 to S. The resulting increase in G1 arrest with p53 activation then contributesto the promotion of apoptotic response upon radiation. Thus, induction of SOCS1 expression may increase therapeuticefficacy of radiation in tumors with low SOCS1 levels.
참고문헌 (25)
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