Inhibition of RelA phosphorylation sensitizes apoptosis in constitutive NF-kappaB-expressing and chemoresistant cells

Cell Death and Differentiation
Sunil K MannaA Sarkar

Abstract

The compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine (P(3)-25) is known to possess anti-bacterial, anti-fungal, anti-tubercular, and local anesthetic activities. We studied the anti-tumorigenic activity of P(3)-25 and the role of nuclear transcription factor kappaB (NF-kappaB) in this process. In constitutive NF-kappaB-expressing cells, treatment with P(3)-25 inhibited the expression of NF-kappaB-dependent reporter gene, adhesion molecules, and cyclooxygenase. It downregulated phosphorylation of p65 by inhibiting upstream kinases, such as protein kinase A and casein kinase II, but did not alter NF-kappaB DNA-binding activity. Alone, P(3)-25 induced apoptosis in NF-kappaB-expressing and doxorubicin-resistant breast cancer cells, and in the presence of other chemotherapeutic agents, it potentiated apoptosis. Overall, our results suggest that P(3)-25 exerts antitumorigenic activity by inhibiting phosphorylation of p65, the transcriptionally active subunit of NF-kappaB by inhibiting its upstream kinases, and potentiates apoptosis mediated by chemotherapeutic agents. These results suggest novel approaches for designing of anticancer drugs for combination chemotherapy.

References

Nov 1, 1996·Science·D J Van AntwerpI M Verma
Oct 16, 1999·The Journal of Biological Chemistry·H SakuraiW Toriumi
Dec 22, 1999·Oncogene·M Barkett, T D Gilmore
Dec 22, 1999·Oncogene·B Rayet, C Gélinas
Jan 24, 2003·Journal of Medicinal Chemistry·Gérard ChauvièreJacques Périé
Jul 16, 2003·Cellular and Molecular Life Sciences : CMLS·C Rüegg, A Mariotti
Jul 31, 2004·World Journal of Gastroenterology : WJG·Ai-Wen WuGuang-Wei Xu
Sep 25, 2004·International Journal of Cancer. Journal International Du Cancer·Paresh MannaSunil K Manna
Oct 12, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kamel IzeradjeneJanet A Houghton
Dec 14, 2004·The Journal of Biological Chemistry·Sunil K Manna, Govindarajan T Ramesh
Jan 18, 2005·Trends in Biochemical Sciences·Karen Heyninck, Rudi Beyaert
Aug 30, 2005·Cellular Signalling·Marit Pedersen DelghandiUgo Moens
Sep 22, 2005·Nature Reviews. Immunology·Michael Karin, Florian R Greten

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Citations

Sep 17, 2008·Journal of Clinical Immunology·Julie S BoseSunil K Manna
Feb 6, 2010·The Journal of Biological Chemistry·Sunil K MannaChitta Sureshkumar
Dec 4, 2010·The Journal of Biological Chemistry·Maikho ThohSunil K Manna
Dec 16, 2010·The Journal of Biological Chemistry·Sunil K MannaMaikho Thoh
Oct 1, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Pattatheyil ArunCarter Van Waes
Jul 19, 2011·International Journal of Food Sciences and Nutrition·Verónica M Heinze, Adriana B Actis
May 12, 2009·Biochemical Pharmacology·Pongali B RaghavendraSunil K Manna
May 1, 2009·Journal of Medicinal Chemistry·Julie S BoseSunil Kumar Manna
Jan 20, 2012·Nature Reviews. Cancer·Neil D Perkins

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis