Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression
Authors: Yizhi Yu
Zhengxin Wang
Runzi Qi
Huazhang An
Nan Li
Chunmei Wang
Xuetao Cao
Qinghua Zhang
Journal: Journal of Biological Chemistry (2009)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Notch signaling; hepatocellular carcinoma; apoptosis; TRAIL; p53
Affiliations: From the National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China., Department of Surgery, Changzheng Hospital, Shanghai 200003, China., Department of Surgery, Changzheng Hospital, Shanghai 200003, China. Electronic address: ., From the National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China. Electronic address: .

Abstract:  Notch signaling plays a critical role in regulating cell proliferation, differentiation, and apoptosis. Our previous study showed that overexpression of Notch1 could inhibit human hepatocellular carcinoma (HCC) cell growth by arresting the cell cycle and inducing apoptosis. HCC cells are resistant to apoptotic induction by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), so new therapeutic approaches have been explored to sensitize HCC cells to TRAIL-induced apoptosis. We are wondering whether and how Notch1 signaling can enhance the sensitivity of HCC cells to TRAIL-induced apoptosis. In this study, we found that overexpression of ICN, the constitutive activated form of Notch1, up-regulated p53 protein expression in HCC cells by inhibiting proteasome degradation. p53 up-regulation was further observed in human primary hepatocellular carcinoma cells after activation of Notch signaling. Inhibition of the Akt/Hdm2 pathway by Notch1 signaling was responsible for the suppression of p53 proteasomal degradation, thus contributing to the Notch1 signaling-mediated up-regulation of p53 expression. Accordingly, Notch1 signaling could make HCC cells more sensitive to TRAIL-induced apoptosis, whereas Notch1 signaling lost the synergistic promotion of TRAIL-induced apoptosis in p53-silenced HepG2 HCC cells and p53-defective Hep3B HCC cells. The data suggest that enhancement of TRAIL-induced apoptosis by Notch1 signaling is dependent upon p53 up-regulation. Furthermore, Notch1 signaling could enhance DR5 expression in a p53-dependent manner. Taken together, Notch1 signaling sensitizes TRAIL-induced apoptosis in HCC cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. Thus, our results suggest that activation of Notch1 signaling may be a promising approach to improve the therapeutic efficacy of TRAIL-resistant HCC. 

Retracted: No

PubPeer comments:
 2020 Expression of Concern. https: www.jbc.org content 295 26 8881 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:] 00541-X fulltext) Retraction on Jan 1, 2021, published online May 13, 2021 VOLUME 284 (2009) PAGES 16183u201316190 This article has been withdrawn by the authors. The Journal states that in Figs. 5B and 5C, a portion of the actin immunoblots were reused in the SMMC7721 panels. In Fig. 6B, si-p53 panel, the p53 immunoblot bands for ICN and parental lanes are duplicated. Also in Fig. 6B, si-p53 panel, the DR5 immunoblot bands for mock and parental lanes are duplicated. In Fig. S1, the Notch 2 and Notch 3 panels are duplicated. The authors state that they disagree with the Journalu2019s findings. This study was conducted nearly 15 years ago. 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 above 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. The authors have indicated that they plan to resubmit their findings elsewhere for publication. ,