Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IkappaBalpha kinase-NFkappaB
Authors: Bai Li
Ning Zhang
Chen Wang
Taoyong Chen
Xiang Lü
Mingjin Yang
Xuetao Cao
Changquan Ling
Journal: Journal of Biological Chemistry (2009)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: apoptosis; cancer drug discovery; TRAIL; melittin; HCC cells
Affiliations: Department of Integrative Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China.

Abstract:  Promoting apoptosis is a strategy for cancer drug discovery. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide range of malignant cells. However, several cancers, including human hepatocellular carcinoma (HCC), exhibit a major resistance to TRAIL-induced cell death. Melittin, a water-soluble 26-amino acid peptide derived from bee venom of Apis mellifera, can exert toxic or inhibitory effects on many types of tumor cells. Here we report that melittin can induce apoptosis of HCC cells by activating Ca2+/calmodulin-dependent protein kinase, transforming growth factor-beta-activated kinase 1 (TAK1), and JNK/p38 MAPK. We show that melittin-induced apoptosis can be inhibited by calcium chelator, by inhibitors for Ca2+/calmodulin-dependent protein kinase, JNK and p38, and by dominant negative TAK1. In the presence of melittin, TRAIL-induced apoptosis is significantly increased in TRAIL-resistant HCC cells, which may be attributed to melittin-induced TAK1-JNK/p38 activation and melittin-mediated inhibition of IkappaBalpha kinase-NFkappaB. Our data suggest that melittin can synergize with TRAIL in the induction of HCC cell apoptosis by activating the TAK1-JNK/p38 pathway but inhibiting the IkappaBalpha kinase-NFkappaB pathway. Therefore, the combination of melittin with TRAIL may be a promising therapeutic approach in the treatment of TRAIL-resistant human cancer. 

Retracted: No

PubPeer comments:
 2020 Expression of Concern. https: www.jbc.org content 295 26 8880 The publisher of the Journal of Biological Chemistry is issuing an Expression of Concern to inform readers that credible concerns have been raised regarding some of the data and conclusions in the article listed above. The Journal of Biological Chemistry will provide additional information as it becomes available. , 
 Retraction on Jan 1, 2021, published online May 22, 2021 https: www.jbc.org article S0021-9258(21)00560-3 fulltext Withdrawal: Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK p38 and inhibiting Iu03baBu03b1 kinase-NFu03baB This article has been withdrawn by the authors. The Journal states that there was inappropriate image manipulation in the top three immunoblots of Fig. 2A. The PARP immunoblot of Fig. 2A also presented duplicated background features. There was inappropriate image manipulation in the cytochrome c immunoblot of Fig. 2C. There was also inappropriate image manipulation in Figs. 4A, 4C, 4E and 4G. Fig. 7F presented several undeclared splices in the first and second panels corresponding to Bcl-xl and c-IAP1. The authors state that they disagree with the Journalu2019s findings. The age of the work and the lack of availability of data storage makes it difficult for the authors to retrieve the requested raw data. The authorsu2019 offer to replace the images in question with those from other experiments under the same conditions was declined by the Journal. The authors state that the issues do not affect the interpretation of the data nor conclusions of this work. The authors state that the conclusions of this article have been confirmed by other independent studies. , 
 In the Good Old Days, JBC provided access to the original versions of papers as submitted by the authors, and often one could deconstruct the images embedded within a PDF, finding that Western Blots were formed by digital composition of overlapping fragments. To their discredit, the new publishers of JBC have removed this feature and deleted all those original PDFs, leaving only the final versions. In the present case, the images in that final PDF are low-resolution and the Internet Archive didn t save the original version, so readers cannot judge the fairness of the claim that  inappropriate manipulation and  undeclared splices were present. ![file] , 
 Similarly, Pubpeer used to provide access to the date a comment was submitted,. The new version of Pubpeer has removed this information. Why? Maybe the only blog or newspaper without that ,