Inhibition of NAMPT pathway by FK866 activates the function of p53 in HEK293T cells.
Inactivation of p53 protein by endogenous and exogenous carcinogens is involved in the pathogenesis of different human malignancies. In cancer associated with SV-40 DNA tumor virus, p53 is considered to be non-functional mainly due to its interaction with the large T-antigen. Using the 293T cell line (HEK293 cells transformed with large T antigen) as a model, we provide evidence that p53 is one of the critical downstream targets involved in FK866-mediated killing of 293T cells. A reduced rate of apoptosis and an increased number of cells in S-phase was accompanied after knockdown of p53 in these cells. Inhibition of NAMPT by FK866, or inhibition of SIRT by nicotinamide decreased proliferation and triggered death of 293T cells involving the p53 acetylation pathway. Additionally, knockdown of p53 attenuated the effect of FK866 on cell proliferation, apoptosis, and cell cycle arrest. The data presented here shed light on two important facts: (1) that p53 in 293T cells is active in the presence of FK866, an inhibitor of NAMPT pathway; (2) the apoptosis induced by FK866 in 293T cells is associated with increased acetylation of p53 at Lys382, which is required for the functional activity of p53.
Department of Pediatrics, Hematology and Oncology, Hannover Medical School, Carl Neuberg Str-1, 30625 Hannover, Germany. thakur.basant@mh-hannover.de
Basant Kumar
BK
Thakur
Tino
T
Dittrich
Prakash
P
Chandra
Annette
A
Becker
Yannick
Y
Lippka
Divakarvel
D
Selvakumar
Jan-Henning
JH
Klusmann
Dirk
D
Reinhardt
Karl
K
Welte
D000107:Acetylation; D000178:Acrylamides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D013539:Simian virus 40; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
D000178:Acrylamides; D016207:Cytokines; D004791:Enzyme Inhibitors; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D016159:Tumor Suppressor Protein p53; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D008239:Lysine