Abstract
Ezrin belongs to the ERM (ezrin-radixin-moesin) protein family and has been demonstrated to regulate early steps of Fas receptor signalling in lymphoid cells, but its contribution to TRAIL-induced cell death regulation in adherent cancer cells remains unknown. In this study we report that regulation of FasL and TRAIL-induced cell death by ezrin is cell type dependant. Ezrin is a positive regulator of apoptosis in T-lymphoma cell line Jurkat, but a negative regulator in colon cancer cells. Using ezrin phosphorylation or actin-binding mutants, we provide evidence that negative regulation of death receptor-induced apoptosis by ezrin occurs in a cytoskeleton- and DISC-independent manner, in colon cancer cells. Remarkably, inhibition of apoptosis induced by these ligands was found to be tightly associated with regulation of ezrin phosphorylation on serine 66, the tumor suppressor gene WWOX and activation of PKA. Deficiency in WWOX expression in the liver cancer SK-HEP1 or the pancreatic Mia PaCa-2 cell lines as well as WWOX silencing or modulation of PKA activation by pharmacological regulators, in the colon cancer cell line SW480, abrogated regulation of TRAIL signalling by ezrin. Altogether our results show that death receptor pro-apoptotic signalling regulation by ezrin can occur downstream of the DISC in colon cancer cells.
Highlights
TNF-Related Apoptosis-Inducing Ligand (TRAIL or Apo2L) induces cell death in a wide variety of cancer cells, but not in normal cells
Inhibited apoptosis induced by TRAIL (S1 Fig)
Ezrin was either stably overexpressed (Fig 1A and 1B) or silenced using siRNA (Fig 1C and 1D) in HCT116 and SW480 cells and apoptosis-induced by TRAIL or Fas ligand was assessed by Hoechst staining
Summary
TNF-Related Apoptosis-Inducing Ligand (TRAIL or Apo2L) induces cell death in a wide variety of cancer cells, but not in normal cells. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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