Colorectal cancer(CRC),a widespread malignancy,is closely associated with tumor microenvironmental hydrogen peroxide(H_(2)O_(2))levels.Some clinical trials targeting H_(2)O_(2)for cancer treatment have revealed its pa...Colorectal cancer(CRC),a widespread malignancy,is closely associated with tumor microenvironmental hydrogen peroxide(H_(2)O_(2))levels.Some clinical trials targeting H_(2)O_(2)for cancer treatment have revealed its paradoxical role as a promoter of cancer progression.Investigating the dynamics of cancer cell H_(2)O_(2)eustress at the single–cell level is crucial.In this study,non–contact hopping probe mode scanning ion conductance microscopy(HPICM)with high-sensitive Pt–functionalized nanoelectrodes was employed to measure dynamic extracellular to intracellular H_(2)O_(2)gradients in individual colorectal cancer Caco–2cells.We explored the relationship between cellular mechanical properties and H_(2)O_(2)gradients.Exposure to 0.1 or 1 mmol/L H_(2)O_(2)eustress increased the extracellular to intracellular H_(2)O_(2)gradient from 0.3 to 1.91 or 3.04,respectively.Notably,cellular F–actin–dependent stiffness increased at 0.1 mmol/L but decreased at 1 mmol/L H_(2)O_(2)eustress.This H_(2)O_(2)–induced stiffness modulated AKT activation positively and glutathione peroxidase 2(GPX2)expression negatively.Our findings unveil the failure of some H_(2)O_(2)-targeted therapies due to their ineffectiveness in generating H_(2)O_(2),which instead acts eustress to promote cancer cell survival.This research also reveals the complex interplay between physical properties and biochemical signaling in cancer cells'antioxidant defense,illuminating the exploitation of H_(2)O_(2)eustress for survival at the single–cell level.Inhibiting GPX and/or catalase(CAT)enhances the cytotoxic activity of H_(2)O_(2)eustress against CRC cells,which holds significant promise for developing innovative therapies targeting cancer and other H_(2)O_(2)-related inflammatory diseases.展开更多
基金supported by Japan Society for the Promotion of Science KAKENHI(21H01770,22K04890)the World Premier International Research Center Initiative(WPI),MEXT,Japan。
文摘Colorectal cancer(CRC),a widespread malignancy,is closely associated with tumor microenvironmental hydrogen peroxide(H_(2)O_(2))levels.Some clinical trials targeting H_(2)O_(2)for cancer treatment have revealed its paradoxical role as a promoter of cancer progression.Investigating the dynamics of cancer cell H_(2)O_(2)eustress at the single–cell level is crucial.In this study,non–contact hopping probe mode scanning ion conductance microscopy(HPICM)with high-sensitive Pt–functionalized nanoelectrodes was employed to measure dynamic extracellular to intracellular H_(2)O_(2)gradients in individual colorectal cancer Caco–2cells.We explored the relationship between cellular mechanical properties and H_(2)O_(2)gradients.Exposure to 0.1 or 1 mmol/L H_(2)O_(2)eustress increased the extracellular to intracellular H_(2)O_(2)gradient from 0.3 to 1.91 or 3.04,respectively.Notably,cellular F–actin–dependent stiffness increased at 0.1 mmol/L but decreased at 1 mmol/L H_(2)O_(2)eustress.This H_(2)O_(2)–induced stiffness modulated AKT activation positively and glutathione peroxidase 2(GPX2)expression negatively.Our findings unveil the failure of some H_(2)O_(2)-targeted therapies due to their ineffectiveness in generating H_(2)O_(2),which instead acts eustress to promote cancer cell survival.This research also reveals the complex interplay between physical properties and biochemical signaling in cancer cells'antioxidant defense,illuminating the exploitation of H_(2)O_(2)eustress for survival at the single–cell level.Inhibiting GPX and/or catalase(CAT)enhances the cytotoxic activity of H_(2)O_(2)eustress against CRC cells,which holds significant promise for developing innovative therapies targeting cancer and other H_(2)O_(2)-related inflammatory diseases.
