title: Involvement of p53 in the cytotoxic activity of the NAMPT inhibitor FK866 in myeloid leukemic cells.
abstract: FK866 is a specific inhibitor of NAMPT and induces apoptosis of leukemic cells by depletion of intracellular NAD(+). Since up-regulation of NAMPT is associated with several cases of cancers, including leukemias, we asked whether in leukemic cells inhibition of NAMPT involves p53 pathway. We observed that FK866 induced apoptosis and reduced cell proliferation in NB-4, OCI-AML3 and MOLM-13 cell lines. In contrast, the leukemia cell lines, K-562 and Kasumi, containing nonfunctional p53 were relatively unaffected by FK866 treatment. Importantly, direct inhibition of sirtuins significantly reduced the viability of NB-4, OCI-AML3 and MOLM-13 cell lines. Activation of p53 by FK866 involved increased acetylation of p53 at lysine 382 with subsequent increase in the expression of p21 and BAX. Further, knockdown of p53 attenuated the effects of FK866 on apoptosis and cell cycle arrest, which was partly associated with decreased expression of p21 and BAX. Our results suggest the role of p53 acetylation pathway in the anti-leukemic effect of FK866.
authors: Department of Pediatric Hematology and Oncology, Hannover Medical School, Carl Neuberg Str-1, 30625 Hannover, Germany. thakur.basant@mh-hannover.de
authors: Basant Kumar
authors: BK
authors: Thakur
authors: Tino
authors: T
authors: Dittrich
authors: Prakash
authors: P
authors: Chandra
authors: Annette
authors: A
authors: Becker
authors: Wolfgang
authors: W
authors: Kuehnau
authors: Jan-Henning
authors: JH
authors: Klusmann
authors: Dirk
authors: D
authors: Reinhardt
authors: Karl
authors: K
authors: Welte
mesh_terms: D000107:Acetylation; D000178:Acrylamides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D016207:Cytokines / Q000037:antagonists & inhibitors*; D055786:Gene Knockout Techniques; D006801:Humans; D007951:Leukemia, Myeloid; D009243:NAD / Q000172:deficiency*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000494:pharmacology*; D037761:Sirtuins / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D000178:Acrylamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D037761:Sirtuins