hPEBP4 resists TRAIL-induced apoptosis of human prostate cancer cells by activating Akt and deactivating ERK1/2 pathways
Authors: Nan Li
Jianming Qiu
Yuanyuan Zhang
Xuetao Cao
Xiaojian Wang
Hongzhe Li
Journal: Journal of Biological Chemistry (2007)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: prostate cancer; hPEBP4; TRAIL resistance; Akt activation; ERK1/2 activation
Affiliations: Institute of Immunology, Zhejiang University, Hangzhou 310031, China.

Abstract:  The treatment options available for prostate cancer are limited because of its resistance to therapeutic agents. Thus, a better understanding of the underlying mechanisms of the resistance of prostate cancer will facilitate the discovery of more efficient treatment protocols. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is recently identified by us as an anti-apoptotic molecule and a potential candidate target for breast cancer treatment. Here we found the expression levels of hPEBP4 were positively correlated with the severity of clinical prostate cancer. Furthermore, hPEBP4 was not expressed in TRAIL-sensitive DU145 prostate cancer cells, but was highly expressed in TRAIL-resistant LNCaP cells, which show highly activated Akt. Interestingly, hPEBP4 overexpression in TRAIL-sensitive DU145 cells promoted Akt activation but inhibited ERK1/2 activation. The hPEBP4-overexpressing DU145 cells became resistant to TRAIL-induced apoptosis consequently, which could be reversed by PI3K inhibitors. In contrast, silencing of hPEBP4 in TRAIL-resistant LNCaP cells inhibited Akt activation but increased ERK1/2 activation, resulting in their sensitivity to TRAIL-induced apoptosis that was restored by the MEK1 inhibitor. Therefore, hPEBP4 expression in prostate cancer can activate Akt and deactivate ERK1/2 signaling, leading to TRAIL resistance. We also demonstrated that hPEBP4-mediated resistance to TRAIL-induced apoptosis occurred downstream of caspase-8 and at the level of BID cleavage via the regulation of Akt and ERK pathways, and that hPEBP4-regulated ERK deactivation was upstream of Akt activation in prostate cancer cells. Considering that hPEBP4 confers cellular resistance to TRAIL-induced apoptosis and is abundantly expressed in poorly differentiated prostate cancer, silencing of hPEBP4 suggests a promising approach for prostate cancer treatment. 

Retracted: Yes

PubPeer comments:
 Concerns about this paper had been reported to the journal in April 2014, but no action has yet been taken. Here are my concerns. Figure 2. Three actin panels in C, E, and F, appear to show lanes that are unexpectedly similar. Labeled in red boxes. Some other lanes look similar too. ![file] , 
 Figure 3A. Some repetitive patterns could be observed in the flow cytometry plots. ![file] , 
 #1 I think the 4 lanes to the right of the red boxes are also the same in the 3 panels. They might be slightly different exposures or perhaps digitally stretched a bit, but to me these look like they are from the same western blot. , 
 September 25 2020 withdrawal. https: www.jbc.org content 295 39 13693.short  This article has been withdrawn by the authors except for Hongzhe Li, who could not be reached. In Fig. 2C, lanes 7 and 14 of the p-ERK1 2 immunoblot are the same. In Fig. 2F, the upper p-ERK1 2 bands in lanes 3 and 4 are the same. Portions of the actin immunoblot from Fig. 2C are reused in Fig. 2, E and F. There are several duplicated features in the FACS plots shown in Fig. 3 (A and B). Portions of the Procaspase 3 immunoblot in Fig. 4B were reused in Procaspase 3 and BID immunoblots in Fig. 4D. The withdrawing authors do not agree with the Journal s analysis of Fig. 2G and Fig. 4 (C and E). The withdrawing authors state that magnification of the bands shows differences that exclude duplication. The withdrawing authors state that they repeated all of the relevant experiments and that the results are the same in their hands. The withdrawing authors state that the issues described above do not affect the interpretation of the data or conclusions of this work. This article characterizes the apoptosis-resistant function, in prostate cancer, of the novel molecule hPEBP4 identified by the authors from breast cancer. The withdrawing authors state that its function and mechanism have been confirmed in prostate cancer and other types of cancer by other independent studies (Li, W., et al. (2016) Biomed. Pharmacother. 81, 1u20136; Huang, R., et al. (2019) Mol. Carcinog. 58, 135u2013143; Zhang, D., et al. (2016) Tumor Biol. 37, 1699u20131705; Huang et al. (2016) J. Neurooncol. 127, 235u2013242; and Liu, H., et al. (2012) Tumor Biol. 33, 267u2013273). The withdrawing authors thus stand by the overall conclusion of the study. , 
 https: retractionwatch.com 2020 09 30 author-says-misguided-efforts-for-the-ideal-western-blot-led-to-the-withdrawal-of-these-studies ,