Why does HAMLET preferentially kill tumor cells? p38-dependent death in tumor but up-regulation of innate immunity in healthy, differentiated cells

HAMLET triggers a p38- and ER stress-dependent death response in carcinoma cells. Transcriptome and proteome analysis detected an increase in p38 expression and phosphorylation exclusively in carcinoma cells and p38 inhibitors delayed the death response to HAMLET in carcinoma and lymphoma cells. ER stress gene expression was also increased in tumor cells and HAMLET triggered rapid XBP1 mRNA splicing, eIF2a phosphorylation, and ATF6 cleavage as well as Hsc70 and CHOP activation, suggesting that ER stress caused by HAMLET may trigger p38 phosphorylation and death. The p38 inhibitor reduced the transcription of both p38 and ER stress gene transcription. Healthy differentiated cells, in contrast, showed no alteration in p38 signaling but a rapid innate immune response was detected and the cells survived HAMLET challenge. 2 cell lines, time course, HAMLET treatment