Leukemia is a cancer of bone marrow or blood cells. The acute myeloid leukemia (AML) is a common subtype occurred in adults to result in death. Forcing malignant cells to undergo differentiation instead of killing cancer cells is one of AML therapeutic strategy. However, the AML patients with poor outcome due to drug resistance is still a challenge. In this study, the abundances of the pro-inflammatory cytokine IL-18 and its receptor (IL-18R) were found to be correlated with the occurrence of drug resistance in AML patients. Importantly, we found that IL-18 induced an anti-apoptotic effect on U937 and THP-1 cells. Cyclooxygenase 2 (COX-2) has been suggested to have an anti-apoptotic role in chemo-resistant cancer cells. IL-18 increased COX-2 expression through post-transcriptional regulation in differentiated U937 cells. We found that two RNA binding proteins, HuR and IMP-3, stabilized COX-2 mRNA expression. In addition, IL-18 induced their interaction and facilitated this complex shuttle from nucleus to cytoplasm. Subsequently, HuR and IMP-3 bound to COX-2 mRNA 3’UTR. Two chemical inhibitors of JNK and ERK1/2 attenuated IL-18-enhanced COX-2 transcripts and the shuttle of HuR from nucleus to cytoplasm. These results suggested that IL-18 stabilized COX-2 mRNA through the JNK- and/or ERK1/2-regulated HuR nucleocytoplasmic shuttling and contributed to an anti-apoptotic effect in AML.

Citation Format: Yu Yi Chu, Chiung Yuan KO, Ju Ming Wang. IL-18 induces an anti-apoptotic effect through stabilizing COX-2 mRNA expression in leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1993.

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.