Modification of the cysteine residues in IkappaBalpha kinase and NF-kappaB (p65) by xanthohumol leads to suppression of NF-kappaB-regulated gene products and potentiation of apoptosis in leukemia cells
Authors: Preetha Anand
Bharat B Aggarwal
Sunil Krishnan
Sushovan Guha
Kuzhuvelil B Harikumar
Kwang S Ahn
Ajaikumar B Kunnumakkara
Journal: Blood (2009)
Discipline: CLINICAL MEDICINE
Keywords: Xanthohumol; apoptosis; NF-kappaB; leukemia; myeloma
Affiliations: Cytokine Research Laboratory, Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA., Cytokine Research Laboratory, Department of Experimental Therapeutics,, Department of Radiation Oncology, and, Department of Gastroenterology, Hepatology and Nutrition, University of Texas M. D. Anderson Cancer Center, Houston

Abstract:  Xanthohumol (XN), a prenylated chalcone isolated from hop plant, exhibits anti-inflammatory, antiproliferative, and antiangiogenic properties through an undefined mechanism. Whether examined by intracellular esterase activity, phosphatidylserine externalization, DNA strand breaks, or caspase activation, we found that XN potentiated tumor necrosis factor-induced apoptosis in leukemia and myeloma cells. This enhancement of apoptosis correlated with down-regulation of nuclear factor-kappaB (NF-kappaB) survivin, bcl-xL, XIAP, cIAP1, cIAP2, cylin D1, and c-myc. XN down-regulated both constitutive and inducible NF-kappaB activation, inhibition of phosphorylation and degradation of IkappaBalpha, suppression of p65 nuclear translocation, and NF-kappaB-dependent reporter gene transcription. XN directly inhibited tumor necrosis factor-induced IkappaBalpha kinase (IKK) activation and a reducing agent abolished this inhibition, indicating the role of cysteine residue. XN had no effect on the IKK activity when cysteine residue 179 of IKK was mutated to alanine. XN also directly inhibited binding of p65 to DNA, a reducing agent reversed this effect, and mutation of cysteine residue 38 to serine of p65 abolished this effect. Thus, our results show that modification of cysteine residues of IKK and p65 by XN leads to inhibition of the NF-kappaB activation pathway, suppression of antiapoptotic gene products, and potentiation of apoptosis in leukemia cells. 

Retracted: No

PubPeer comments:
 This EoC does not seem to appear on the original article s main page.  The Editors wish to express their concern about the 26 February 2009 article cited above, regarding the reliability and or veracity of the data and the study outcomes while awaiting the conclusions of the institutional investigation, specifically for the results shown in Figure 5A. Four of the panels show cell and nuclei images that are identical to panels from Figure 2D of Ajaikumar B. Kunnumakkara, Haruyo Ichikawa, Preetha Anand, Chiramel J. Mohankumar, Padmanabhan S. Hema, Mangalam S. Nair, and Bharat B. Aggarwal, u201cCoronarin D, a labdane diterpene, inhibits both constitutive and inducible nuclear factor-u03baB pathway activation, leading to potentiation of apoptosis, inhibition of invasion, and suppression of osteoclastogenesisu201d [Mol Cancer Ther. 2008;7(10):3306-3317], and the authors now purport that they represent the experiments published in that article and not those described in the Blood article. In Figure 5B, the TNG and TNF+XN actin blot bands appear to be identical, which cannot be correct, because the cells were harvested under different conditions. The primary data for these experiments have not been located. Should additional information become available about the conduct of this study, the Journal will evaluate that information carefully and determine whether additional notifications will be necessary. ,