Abstract
Nuclear transcription factor kappa B (NF-κB) has been shown both to block apoptosis and to promote cell proliferation, and hence has been considered an important target for anticancer drug development. The pyrimidine analogue cytosine arabinoside (araC) is among the most effective agents used in the treatment of acute leukemia, and we demonstrate in this study that its chemotherapeutic activity may be mediated by its inhibition of NF-κB. We found that in Jurkat cells, although tumor necrosis factor (TNF), araC, or ceramide induced NF-κB, the induction was only transient in the case of araC. In both HuT-78 and serum-activated LPS-stimulated Jurkat (SA-LPS/Jkt) cells that expressed NF-κB, TNF or ceramide treatments did not affect the NF-κB expression whereas araC downregulated it. AraC, but not TNF or ceramide was able to induce apoptosis in these cells as detected by assays for lipid peroxidation, reactive oxygen intermediates generation, caspase activation, cytotoxicity, Bcl-2 degradation, and DNA fragmentation. AraC also potentiated apoptosis mediated by cis-platin, etoposide, or taxol in these cells. AraC was able to induce protein phosphatases (PP) 2A and 2B-A, and phosphorylation of p65 subunit of NF-κB in the HuT-78 and SA-LPS/Jkt cells was downregulated by araC treatment. Furthermore, calyculin A, a specific phospho-serine/phospho-threonine phosphatase inhibitor, protected HuT-78 and SA-LPS/Jkt cells from araC-mediated NF-κB downregulation and apoptosis. These observations collectively suggest that araC induces apoptosis in NF-κB-expressing cells by dephosphorylating the p65 subunit of NF-κB.
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Acknowledgements
We thank Drs S Mahalingam, G Ramakrishna, R Sen, S Khosla, J Gowrishankar, and SE Hasnain for critically and carefully reading the manuscript. This work was supported by the Department of Biotechnology (DBT), Govt of India. We duly acknowledge CSIR, Govt of India for providing fellowships for YS and AS.
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Sreenivasan, Y., Sarkar, A. & Manna, S. Mechanism of cytosine arabinoside-mediated apoptosis: role of Rel A (p65) dephosphorylation. Oncogene 22, 4356–4369 (2003). https://doi.org/10.1038/sj.onc.1206486
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DOI: https://doi.org/10.1038/sj.onc.1206486
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