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

Syed Shoeb Razvi; Hani Choudhry; Mohammed Nihal Hasan; Mohammed A Hassan; Said Salama Moselhy; Khalid Omer Abualnaja; Mazin A Zamzami; Taha Abduallah Kumosani; Abdulrahman Labeed Al-Malki; Majed A Halwani; Abdulkhaleg Ibrahim; Ali Hamiche; Christian Bronner; Tadao Asami; Mahmoud Alhosin

doi:10.1177/2516865718814543

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

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

Authors

Syed Shoeb Razvi¹, Hani Choudhry^{1

2

3

4}, Mohammed Nihal Hasan¹, 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 Halwani⁹, Abdulkhaleg Ibrahim¹⁰, Ali Hamiche¹⁰, Christian Bronner¹⁰, Tadao Asami^{1

11}, Mahmoud Alhosin^{1

2

3}

Affiliations

¹ Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
² Cancer Metabolism and Epigenetic Unit, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
³ Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
⁴ Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
⁵ Department of Basic Medical Sciences, College of Medicine and Health Sciences, Hadhramout University, Mukalla, Yemen.
⁶ Bioactive Natural Products Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
⁷ Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
⁸ Production of Bioproducts for Industrial Applications Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
⁹ Nanomedicine Department, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
¹⁰ Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258 CNRS UMR 7104, Université de Strasbourg, Illkirch, France.
¹¹ Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.

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.