Identification of Deregulated Signaling Pathways in Jurkat Cells in Response to a Novel Acylspermidine Analogue-N4-Erucoyl Spermidine.

Abstract

Natural polyamines such as putrescine, spermidine, and spermine are crucial in the cell proliferation and maintenance in all the eukaryotes. However, the requirement of polyamines in tumor cells is stepped up to maintain tumorigenicity. Many synthetic polyamine analogues have been designed recently to target the polyamine metabolism in tumors to induce apoptosis. N⁴-Erucoyl spermidine (designed as N⁴-Eru), a novel acylspermidine derivative, has been shown to exert selective inhibitory effects on both hematological and solid tumors, but its mechanisms of action are unknown. In this study, RNA sequencing was performed to investigate the anticancer mechanisms of N⁴-Eru-treated T-cell acute lymphoblastic leukemia (ALL) cell line (Jurkat cells), and gene expression was examined through different tools. We could show that many key oncogenes including NDRG1, CACNA1G, TGFBR2, NOTCH1,2,3, UHRF1, DNMT1,3, HDAC1,3, KDM3A, KDM4B, KDM4C, FOS, and SATB1 were downregulated, whereas several tumor suppressor genes such as CDKN2AIPNL, KISS1, DDIT3, TP53I13, PPARG, FOXP1 were upregulated. Data obtained through RNA-Seq further showed that N⁴-Eru inhibited the NOTCH/Wnt/JAK-STAT axis. This study also indicated that N⁴-Eru-induced apoptosis could involve several key signaling pathways in cancer. Altogether, our results suggest that N⁴-Eru is a promising drug to treat ALL.