Prostaglandin (PG) A2, a cyclopentenone PG, induced apoptosis in both HCT116 and HCT116 p53 −/− cells. Although PGA2-induced apoptosis in HCT116 cells was dependent on the p53-DR5 pathway, the mechanism underlying PGA2-induced apoptosis in HCT116 p53 −/− cells remains unknown. In this study, we observed that PGA2 caused an increase of mRNA expression of DR5 and protein expression even in HCT116 p53 −/− cells, accompanied by caspase-dependent apoptosis. Knockdown of DR5 expression by RNA interference inhibited PGA2-induced apoptosis in HCT116 p53 −/− cells. Parallel to the induction of apoptosis, PGA2 treatment upregulated expression of genes upstream of DR5 such as ATF4 and CHOP. Knockdown of CHOP prevented DR5-dependent cell death as well as the expression of DR5 protein. Furthermore, knockdown of ATF4 by RNA interference decreased both mRNA and protein levels of CHOP and DR5, thereby suppressing PGA2-induced cell death. Consistently, the DR5 promoter activity increased by PGA2 was not stimulated when the CHOP binding site in the DR5 promoter was mutated. These results collectively suggest that PGA2 may induce DR5-dependent apoptosis via the ATF4-CHOP pathway in HCT116 p53 null cells.