Stomach cancer-derived del223V-226L mutation of the STCH gene causes loss of sensitization to TRAIL-mediated apoptosis

The stress 70 protein chaperone (STCH), a member of the heat shock protein 70 (HSP70) superfamily, is a microsomal protein that contains a N-terminal ATPase domain but lacks a C-terminal protein binding domain. Although cell-protective functions of HSP70 members are well characterized, the biological relevance of STCH remains unclear. We previously identified STCH as a candidate gene for Susceptibility to stomach cancer by genetic analyses. In this study, we searched somatic mutations of STCH in human stomach cancer and identified the 668del12bp mutation in exon 4, resulting in a four amino acid deletion (de1223 V-226L) in the conserved ATP-binding domain. In vitro binding assays revealed that this mutant lacks ATP-binding activity. Overexpression of wild-type STCH sensitized cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death, whereas del223V-226L mutant did not show any effect. These results suggest that STCH has a role in cell survival via modulation of the TRAIL-mediated cell death pathway. (c) 2008 Elsevier Inc. All rights reserved.