RETRACTED ARTICLE: Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b+/Gr-1+ myeloid derived suppressor cells
Authors: Qingjun Liu
Andrew K Geissler
James W Mier
David J Panka
Journal: Molecular Cancer (2013)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: p53; VEGF-targeted therapy; renal cell carcinoma; HDM2 antagonist; sunitinib
Affiliations: Division of Hematology-Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. 

Abstract:  Background: The studies reported herein were undertaken to determine if the angiostatic function of p53 could be exploited as an adjunct to VEGF-targeted therapy in the treatment of renal cell carcinoma (RCC). Methods: Nude/beige mice bearing human RCC xenografts were treated with various combinations of sunitinib and the HDM2 antagonist MI-319. Tumors were excised at various time points before and during treatment and analyzed by western blot and IHC for evidence of p53 activation and function. Results: Sunitinib treatment increased p53 levels in RCC xenografts and transiently induced the expression of p21(waf1), Noxa, and HDM2, the levels of which subsequently declined to baseline (or undetectable) with the emergence of sunitinib resistance. The development of resistance and the suppression of p53-dependent gene expression temporally correlated with the induction of the p53 antagonist HDMX. The concurrent administration of MI-319 markedly increased the antitumor and anti-angiogenic activities of sunitinib and led to sustained p53-dependent gene expression. It also suppressed the expression of the chemokine SDF-1 (CXCL12) and the influx of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) otherwise induced by sunitinib. Although p53 knockdown markedly reduced the production of the angiostatic peptide endostatin, the production of endostatin was not augmented by MI-319 treatment. Conclusions: The evasion of p53 function (possibly through the expression of HDMX) is an essential element in the development of resistance to VEGF-targeted therapy in RCC. The maintenance of p53 function through the concurrent administration of an HDM2 antagonist is an effective means of delaying or preventing the development of resistance. 

Retracted: Yes

PubPeer comments:
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 https: retractionwatch.com 2020 11 24 former-harvard-cancer-researcher-faked-a-dozen-images-say-feds , 
 2021 retraction. https: molecular-cancer.biomedcentral.com articles 10.1186 s12943-021-01379-7 Retraction Note to: Mol Cancer 12, 17 (2013) https: doi.org 10.1186 1476-4598-12-17 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 1 (reuse of the bands in the fourth to fifth lanes of the second row representing noxa expression in the control group of A498 cell type, to falsely represent noxa expression in the sunitinib resistant group of A498 cells in the same figure, eleventh to twelfth lanes of the second row) Reuse and relabelling of the same source bands to falsely represent different experimental results in Figure 1 (reuse of the band in the eighth lane of the second row representing noxa expression in the third sample of the sunitinib responding group, to falsely represent noxa expression in the fifth sample of the sunitinib responding group in the same figure, tenth lane of the second row Reuse and relabelling of the same source bands to falsely represent different experimental results in Figure 6B (first two lanes of the bottom row representing vinculin expression in control group, and eleventh and twelfth lanes of the bottom row representing vinculin expression in dox + sunitinib group) Andrew K Geissler and James W Mier agree 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. ,