Abstract
Colorectal cancer(CRC),a widespread malignancy,is closely associated with tumor microenvironmental hydrogen peroxide(H2O2)levels.Some clinical trials targeting H2O2 for cancer treatment have revealed its paradoxical role as a promoter of cancer progression.Investigating the dynamics of cancer cell H2O2 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 H2O2 gradients in individual colorectal cancer Caco-2 cells.We explored the relationship between cellular mechanical properties and H2O2 gradients.Exposure to 0.1 or 1 mmol/L H2O2 eustress increased the extracellular to intracellular H2O2 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 H2O2 eustress.This H2O2-induced stiffness modulated AKT activation posi-tively and glutathione peroxidase 2(GPX2)expression negatively.Our findings unveil the failure of some H2O2-targeted therapies due to their ineffectiveness in generating H2O2,which instead acts eustress to promote cancer cell survival.This research also reveals the complex interplay between physical proper-ties and biochemical signaling in cancer cells'antioxidant defense,illuminating the exploitation of H2O2 eustress for survival at the single-cell level.Inhibiting GPX and/or catalase(CAT)enhances the cytotoxic activity of H2O2 eustress against CRC cells,which holds significant promise for developing innovative therapies targeting cancer and other H2O2-related inflammatory diseases.
基金项目
Japan Society for the Promotion of Science KAKENHI(21H01770)
Japan Society for the Promotion of Science KAKENHI(22K04890)
World Premier International Research Center Initiative(WPI),MEXT,Japan()
NETL
NSTL
万方数据