Inhibition of Jurkat T Cell Growth by N-farnesyl-norcantharimide Through Up-regulation of Tumor Suppressor Genes and Down-regulation of Genes for Steroid Biosynthesis, Metabolic Pathways and Fatty Acid Metabolism

Abstract

Background/Aim: To evaluate the anti-cancer mechanism of . Materials and Methods: The viability of NC15-treated human leukemic Jurkat T (JKT) cells was assessed using the Kit-8 cell counting method. Flow cytometry analysis, human apoptosis antibody array assay, and whole genome sequencing were adopted to investigate the mechanism underlying the anti-cancer activity of NC15 in JKT cells. Results: The growth inhibition rates of NC15 in JKT cells were about 80% and 95% after treatment with 8 μmol/l NC15 for 24 and 48 h, respectively. The percentages of NC15-treated JKT cells in the sub-G 1 phase at 24 and 48 h were 22.0% and 34.3%, respectively, in contrast to the 1.5% in the control. Next-generation sequencing showed that many tumor suppressor genes (TSG) were up-regulated, while many genes associated with steroid biosynthesis, metabolic pathways, and fatty acid metabolism were downregulated. Conclusion: NC15 can reduce the cell viability and increase the percentage of JKT cells in the sub-G 1 phase by up-regulating TSG and related genes, and down-regulating the genes for steroid biosynthesis, metabolic pathways and fatty acid metabolism, instead of through apoptosis. Acute T lymphoblastic leukemia (T-ALL) is one of the most common childhood cancers with very poor prognosis (1). A quarter of childhood T-ALL patients have relapsed within 5 years of treatment with very poor prognosis (2). The survival rate of patients with T-ALL within 5 years is less than 25%(3). Therefore, it is necessary to search for more efficient yet less toxic anti-cancer drugs for leukemia.The Jurkat T (JKT) cell line established from the peripheral blood of a 14 years old boy with T-ALL in the late 1970s was used in this study (4). Phorbol 12-myristate 13acetate plus ionomycin (PMA + ION) are often used in the study of the underlying mechanism of anti-cancer drugs because PMA + ION can activate JKT cells to produce high levels of interleukin-2 (IL-2) (5-8), and activate the JKT cells via a PKC-Ras signaling pathway (7,8).Mylabris, a species of blister beetle (Mylabris phalerata Pall.), has been used in the treatment of many kinds of malignancies in traditional oriental medicine for two thousand years (9-12). Mylabris-derived Cantharidin is a potent serine/threonine protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) inhibitor (13)(14)(15). Though Cantharidin has anti-cancer properties (16,17), its clinical applications are limited because of its toxicity towards the kidneys and the urinary system (18,19).

Orchestral role of lipid metabolic reprogramming in T-cell malignancy

“…The inhibition of CPT1A and associated FAO in leukemia cells by etomoxir or ranolazine augmented the efficacy of ABT-737-mediated cell death through pro-apoptotic Bak protein ( 124 ). The inhibition of leukemic T cells by N -farnesyl-norcantharimide (NC15) correlates with alteration in fatty acid metabolism genes ( 215 ). Moreover, resistant T-ALL cells show an altered rate and relatively high dependence on FAO over exogenous glutamine ( 71 ).…”

The prognostic value of MicroRNAs associated with fatty acid metabolism in head and neck squamous cell carcinoma

“…Furthermore, changing lipid availability influences cancer cell motility, angiogenesis development, metabolic symbiosis, immune surveillance evasion, and cancer medication resistance. The reprogramming of fatty acid metabolism in tumor tissues has attracted a lot of attention as a possible cancer therapeutic target ( Pacella et al, 2018 ; Wu J. Y. et al, 2020 ; Wu L. et al, 2020 ). Recently, the relevance of tumor metabolism in HNSCC and its surrounding environment has gained more attention.…”

Apoptotic induction of the water fraction of Pseuderanthemum palatiferum ethanol extract powder in Jurkat cells monitored by FTIR microspectroscopy

“…Jurkat cells are an immortalized human T lymphocyte cell line originally established from peripheral blood of a 14-year-old boy with relapsed acute lymphoblastic leukemia (ALL) [2]. The Jurkat cell line has been the most often used as acute T cell leukemia to verify the therapeutic potential of anti-cancer compounds [3][4][5]. Throughout history, plants have been valuable sources for novel anti-cancer drugs [6].…”