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

J. Biol. Chem., Vol. 283, Issue 6, 3349-3356, February 8, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/6/3349    most recent M707773200v1 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 Google Scholar Google Scholar Articles by Xie, Y. Articles by Qiu, Y. Search for Related Content PubMed PubMed Citation Articles by Xie, Y. Articles by Qiu, Y. Social Bookmarking                      What's this?

The 44-kDa Pim-1 Kinase Phosphorylates BCRP/ABCG2 and Thereby Promotes Its Multimerization and Drug-resistant Activity in Human Prostate Cancer Cells^*

Yingqiu Xie, Kexin Xu, Douglas E. Linn¹, Xi Yang, Zhiyong Guo, Hermela Shimelis, Takeo Nakanishi^¶, Douglas D. Ross^¶||**, Hegang Chen, Ladan Fazli, Martin E. Gleave, and Yun Qiu^¶2

From the Departments of Pharmacology and Experimental Therapeutics, Medicine, ^||Pathology, and Epidemiology & Preventive Medicine, and the ^¶The Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, ^**The Baltimore Veterans Affair Medical Center, Baltimore, Maryland 21201, and The Prostate Center, Vancouver General Hospital, Vancouver, British Columbia V6H 3Z6, Canada

We previously showed that the 44-kDa serine/threonine kinase Pim-1 (Pim-1L) can protect prostate cancer cells from apoptosis induced by chemotherapeutic drugs (Xie, Y., Xu, K., Dai, B., Guo, Z., Jiang, T., Chen, H., and Qiu, Y. (2006) Oncogene 25, 70–78). To further explore the mechanisms of Pim-1L-mediated resistance to chemotherapeutic drugs in prostate cancer cells, we employed a yeast two-hybrid screening to identify cellular proteins that were associated with Pim-1L, and we found the ABC transporter BCRP/ABCG2 as one of the potential interacting partners of Pim-1L. We also showed that the expression level of Pim-1L and BCRP was up-regulated in mitoxantrone and docetaxel-resistant prostate cancer cell lines. Pim-1L was co-localized with BCRP on the plasma membrane and induced phosphorylation of BCRP at threonine 362. Knocking-down Pim-1L expression in the drug-resistant prostate cancer cells abolished multimer formation of endogenous BCRP and resensitized the resistant cells to chemotherapeutic drugs suggesting that BCRP phosphorylation induced by Pim-1L was essential for its functionality. This is further corroborated by our finding that the plasma membrane localization and drug-resistant activity of BCRP were compromised by T362A mutation. Our data suggest that Pim-1L may protect prostate cancer cells from apoptosis, at least in part, through regulation of transmembrane drug efflux pump. These findings may provide a potential therapeutic approach by disrupting Pim-1 signaling to reverse BCRP-mediated multidrug resistance.

Received for publication, September 17, 2007 , and in revised form, December 4, 2007.

^* This work was supported in part by National Institutes of Health Grant CA106504, Department of Defense (DOD) Grants DAMD17-03-1-0117, W81XWH-06-1-0199), and the award from Prostate Cancer Foundation (to Y. Q.), the DOD Pre-doctoral Fellowship (W81XWH-06-1-0005) (to K. X.), a Veterans Affairs merit review grant (to D. D. R.), and a pilot grant from the Greenebaum Cancer Center (to Y. Q., D. D. R., and T. N.). 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 Supported by the NIEHS, National Institutes of Health Training Grant T32ES07263.

² To whom correspondence should be addressed: Dept. of Pharmacology & Experimental Therapeutics, University of Maryland School of Medicine, 655 W Baltimore St., BRB Rm. 4-002, Baltimore, MD 21202. Fax: 410-706-0032; E-mail: yqiu{at}som.umaryland.edu.

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