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. 2018 Nov 27:11:2516865718814543.
doi: 10.1177/2516865718814543. eCollection 2018.

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

Syed Shoeb Razvi  1 , Hani Choudhry  1   2   3   4 , Mohammed Nihal Hasan  1 , Mohammed A Hassan  1   5 , Said Salama Moselhy  1   4   6   7 , Khalid Omer Abualnaja  1   4   6 , Mazin A Zamzami  1   2   3 , Taha Abduallah Kumosani  1   4   8 , Abdulrahman Labeed Al-Malki  1   4   6 , Majed A Halwani  9 , Abdulkhaleg Ibrahim  10 , Ali Hamiche  10 , Christian Bronner  10 , Tadao Asami  1   11 , Mahmoud Alhosin  1   2   3
Affiliations

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

Syed Shoeb Razvi et al. Epigenet Insights. .

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.

Keywords: ALL; Acylspermidine; Jurkat; RNA-Seq; anticancer; gene expression; polyamine.

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Conflict of interest statement

Declaration of conflicting interests:The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership, grants, or patents received or pending and royalties. No writing assistance was used in the production of this manuscript.

Figures

Figure 1.
Figure 1.
Annotation statistics of downregulated GO terms of the N4-Eru-treated Jurkat cells. The length of the bar represents the significance of that specific gene set or term. In addition, the degree of the brightness of the color denotes the significance (P < .01) of the differentially expressed genes.
Figure 2.
Figure 2.
Annotation statistics of upregulated GO terms of the N4-Eru-treated Jurkat cells. The length of the bar represents the significance of that specific gene set or term. In addition, the degree of the brightness of the color denotes the significance (P < .01) of the differentially expressed genes.
Figure 3.
Figure 3.
KEGG pathway analysis of differentially regulated genes in Jurkat cells after treatment with N4-Eru, depicting the affected genes in Notch signaling pathway.
Figure 4.
Figure 4.
Significant deregulated key signaling nodes of JAK-STAT signaling pathway are represented in Jurkat cells after treatment with N4-Eru. Biocarta pathway analysis of critical differentially expressed genes is depicted with an asterisk.
Figure 5.
Figure 5.
Significant deregulated key signaling nodes of JAK-Wnt signaling axis are represented in Jurkat cells after treatment with N4-Eru. KEGG pathway analysis of differentially expressed genes is depicted with an asterisk.
Figure 6.
Figure 6.
Different gene interactions of the most significantly deregulated differentially expressed genes are represented as strings depicting cell death and tumor suppressor genes in N4-Eru-treated Jurkat cells as compared with untreated cells.
Figure 7.
Figure 7.
The heat map of the significantly altered differentially expressed genes shows the change with the intensity of the color varying with the alteration of LogFC (fold change) from −6 to +6 in N4-Eru-treated Jurkat cells as compared with untreated cells.
See this image and copyright information in PMC

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