Caveolin-1 regulates the ASMase/ceramide-mediated radiation response of endothelial cells in the context of tumor-stroma interactions.

摘要: The integral membrane protein caveolin-1 (CAV1) plays a central role in radioresistance-mediating tumor–stroma interactions of advanced prostate cancer (PCa). Among the tumor–stroma, endothelial cells (EC) evolved as critical determinants radiation response. CAV1 deficiency angiogenic EC was already shown to account for increased apoptosis rates irradiated EC. This study explores potential impact differential levels on acid sphingomyelinase (ASMase)/ceramide pathway key player regulation upon irradiation and cell radioresistance. Enhanced sensitivity CAV1-deficient associated with ASMase activity, ceramide generation, formation large lipid platforms, finally an altered p38 mitogen-activated kinase (MAPK)/heat-shock 27 (HSP27)/AKT (protein B, PKB) signaling. growth delay LNCaP PC3 PCa treatment direct 3D spheroid co-cultures. Exogenous C6 C16 parallel spheroids induced apoptosis. Analysis respective species like those typically found radio-resistant tumors further revealed upregulation unsaturated C24:1 that might scavenge effects EC-derived apoptosis-inducing ceramide. Higher well could be confirmed by immunohistochemistry human specimen bearing characteristic alterations. Conclusively, critically regulates generation ceramide-dependent (re-)organization plasma turn affects response adjacent cells. Understanding CAV1-dependent crosstalk between tumor host-derived microvasculature its radiosensitivity may allow define rational strategy overcoming resistance improving clinical outcomes targeting CAV1.