HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 7, 4943-4950, February 16, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/7/4943    most recent M609494200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, H. Articles by Cao, X. Search for Related Content PubMed PubMed Citation Articles by Li, H. Articles by Cao, X. Social Bookmarking                      What's this?

hPEBP4 Resists TRAIL-induced Apoptosis of Human Prostate Cancer Cells by Activating Akt and Deactivating ERK1/2 Pathways^*

Hongzhe Li¹, Xiaojian Wang¹, Nan Li^¶1, Jianming Qiu, Yuanyuan Zhang, and Xuetao Cao^¶2

From the Institute of Immunology, Zhejiang University, Hangzhou 310031, China, the Institute of Immunology, Tsinghua University School of Medicine, Beijing 100084, China, and the ^¶Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China

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.

Received for publication, October 10, 2006 , and in revised form, November 15, 2006.

^* This work was supported in part by Grants from the National Natural Science Foundation of China (30600747, 30121002, 30490240), Tsinghua-Yue-Yuen Medical Sciences Fund (202400.005-02), the National Key Basic Research Program of China (2001CB510002), and the National High Biotechnology Development Program of China (2002BA711A01). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Inst. of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. Fax: 86-21-6538-2502; E-mail: caoxt{at}public3.sta.net.cn.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Wang, T. Chen, N. Zhang, M. Yang, B. Li, X. Lu, X. Cao, and C. Ling 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 I{kappa}B{alpha} Kinase-NF{kappa}B J. Biol. Chem., February 6, 2009; 284(6): 3804 - 3813. [Abstract] [Full Text] [PDF]

				F. Haimerl, A. Erhardt, G. Sass, and G. Tiegs Down-regulation of the De-ubiquitinating Enzyme Ubiquitin-specific Protease 2 Contributes to Tumor Necrosis Factor-{alpha}-induced Hepatocyte Survival J. Biol. Chem., January 2, 2009; 284(1): 495 - 504. [Abstract] [Full Text] [PDF]

				B. C. Kim, M. S. Ryu, S. P. Oh, and I. K. Lim TIS21/BTG2 Negatively Regulates Estradiol-Stimulated Expansion of Hematopoietic Stem Cells by Derepressing Akt Phosphorylation and Inhibiting mTOR Signal Transduction Stem Cells, September 1, 2008; 26(9): 2339 - 2348. [Abstract] [Full Text] [PDF]