RETRACTED ARTICLE:Differential modulatory effects of GSK-3β and HDM2 on sorafenib-induced AIF nuclear translocation (programmed necrosis) in melanoma
Authors: Qingjun Liu
David J Panka
James W Mier
Journal: Molecular Cancer (2011)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: GSK-3β; p53; sorafenib; MI-319; cytotoxicity
Affiliations: Division of Hematology-Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

Abstract:  Background: GSK-3β phosphorylates numerous substrates that govern cell survival. It phosphorylates p53, for example, and induces its nuclear export, HDM2-dependent ubiquitination, and proteasomal degradation. GSK-3β can either enhance or inhibit programmed cell death, depending on the nature of the pro-apoptotic stimulus. We previously showed that the multikinase inhibitor sorafenib activated GSK-3β and that this activation attenuated the cytotoxic effects of the drug in various BRAF-mutant melanoma cell lines. In this report, we describe the results of studies exploring the effects of GSK-3β on the cytotoxicity and antitumor activity of sorafenib combined with the HDM2 antagonist MI-319. Results: MI-319 alone increased p53 levels and p53-dependent gene expression in melanoma cells but did not induce programmed cell death. Its cytotoxicity, however, was augmented in some melanoma cell lines by the addition of sorafenib. In responsive cell lines, the MI-319/sorafenib combination induced the disappearance of p53 from the nucleus, the down modulation of Bcl-2 and Bcl-xL, the translocation of p53 to the mitochondria and that of AIF to the nuclei. These events were all GSK-3β-dependent in that they were blocked with a GSK-3β shRNA and facilitated in otherwise unresponsive melanoma cell lines by the introduction of a constitutively active form of the kinase (GSK-3β-S9A). These modulatory effects of GSK-3β on the activities of the sorafenib/MI-319 combination were the exact reverse of its effects on the activities of sorafenib alone, which induced the down modulation of Bcl-2 and Bcl-xL and the nuclear translocation of AIF only in cells in which GSK-3β activity was either down modulated or constitutively low. In A375 xenografts, the antitumor effects of sorafenib and MI-319 were additive and associated with the down modulation of Bcl-2 and Bcl-xL, the nuclear translocation of AIF, and increased suppression of tumor angiogenesis. Conclusions: Our data demonstrate a complex partnership between GSK-3β and HDM2 in the regulation of p53 function in the nucleus and mitochondria. The data suggest that the ability of sorafenib to activate GSK-3β and alter the intracellular distribution of p53 may be exploitable as an adjunct to agents that prevent the HDM2-dependent degradation of p53 in the treatment of melanoma. 

Retracted: Yes

PubPeer comments:
null, 
null, 
null, 
 https: retractionwatch.com 2020 11 24 former-harvard-cancer-researcher-faked-a-dozen-images-say-feds , 
 https: grants.nih.gov grants guide notice-files NOT-OD-21-037.html , 
 2021 retraction. https: molecular-cancer.biomedcentral.com articles 10.1186 s12943-021-01378-8 The Editor-in-Chief has retracted this article after an investigation by Harvard Medical School and Beth Israel Deaconess Medical Center and additional analysis by the Office of Research Integrity found: Reuse and relabelling of the same source bands to falsely represent different experimental results in Figure 3A (first four lanes in the middle row of the left panel representing c-myc expression in nucleus of A375 cell type, and first four lanes in the middle row of the right panel representing c-myc expression in nucleus of SK MEL 5 cell type) Reuse and relabelling of the same source bands to falsely represent different experimental results in Figure 5 (sixth to eighth lanes of the middle row representing BCL-XL expression in A375-GSK cells with DOX, and last three lanes of the middle row representing BCL-XL expression in SK MEL 5 S9A) Reuse and relabelling of unrelated source bands falsely represent different experimental results in Figure 5 (thirteenth to fifteenth lanes of the top row representing BCL2 expression in SK MEL 5 S9A, and thirteenth to fifteenth lanes of the bottom row representing VINCULIN expression in SK MEL 5 S9A) James W Mier agrees with this retraction. David J Panka does not agree with this retraction. The Editor-in-Chief has not been able to find a current email address for Qingjun Liu. ,