JNK MAPK Regulates IFN-Stimulated Genes and Cell Adhesion in Chemoresistant, Quiescent Leukemic Cells

Abstract

AbstractCancer cells survive environmental stresses including DNA damage-inducing chemotherapy by entering cellular quiescence (G0). In our previous study, to elucidate how G0 leukemic cells become resistant to chemotherapy, we profiled them at the transcriptome, translatome and proteome levels. Here, we used these datasets to identify differentially expressed genes and find that IFN-stimulated genes are highly expressed in our G0 models of leukemic cells induced by AraC chemotherapy or serum-starvation. Mechanistically, upon induction of G0, STAT1 is phosphorylated on tyrosine 701, leading to transcription of IFN-stimulated genes. Importantly, our data reveal that activation of JNK and p38 MAPK is integral to STAT1 phosphorylation and expression of IFN-stimulated genes. Pharmacological inhibition of either JNK or p38 MAPK greatly reduced expression of IFN-stimulated genes as well as STAT1 phosphorylation, revealing a JNK-STAT1 pathway that regulates IFN-stimulated genes. While the expression of IFN-stimulated genes does not affect survival rates of patients with hematological malignancies and chemoresistance of G0 leukemic cells, we find that this JNK-STAT1 pathway enhances adherence of G0 leukemic cells. Consistently, inhibition of the JNK-STAT1 pathway dramatically reduced the number of adherent G0 cells. Interestingly, STAT1 is transiently phosphorylated within 24 hours of chemotherapy, leading to transcriptional expression of IFN-stimulated genes. Subsequently, post 24 hours of chemotherapy, translational regulation attenuates their expression, thereby enabling precisely controlled expression of IFN-stimulated genes in G0 leukemic cells. These studies uncover translational and transcriptional regulation of IFN-stimulated genes by a JNK-STAT1 pathway that enhances cell adhesion in G0 leukemic cells.