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J. Biol. Chem., Vol. 283, Issue 30, 20635-20644, July 25, 2008

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The PIM1 Kinase Is a Critical Component of a Survival Pathway Activated by Docetaxel and Promotes Survival of Docetaxel-treated Prostate Cancer Cells^*

Marina Zemskova, Eva Sahakian, Svetlana Bashkirova, and Michael Lilly¹

From the Center for Health Disparities and Molecular Medicine, Departments of Medicine and Microbiology, Loma Linda University School of Medicine, Loma Linda, California 92354 and Chao Family Comprehensive Cancer Center, University of California, Irvine, California 92868

A defining characteristic of solid tumors is the capacity to divide aggressively and disseminate under conditions of nutrient deprivation, limited oxygen availability, and exposure to cytotoxic drugs or radiation. Survival pathways are activated within tumor cells to cope with these ambient stresses. We here describe a survival pathway activated by the anti-cancer drug docetaxel in prostate cancer cells. Docetaxel activates STAT3 phosphorylation and transcriptional activity, which in turns induces expression of the PIM1 gene, encoding a serine-threonine kinase activated by many cellular stresses. Expression of PIM1 improves survival of docetaxel-treated prostate cancer cells, and PIM1 knockdown or expression of a dominant-negative PIM1 protein sensitize cells to the cytotoxic effects of docetaxel. PIM1 in turn mediates docetaxel-induced activation of NFB transcriptional activity, and PIM1 depends in part on RELA/p65 proteins for its prosurvival effects. The PIM1 kinase plays a critical role in this STAT3 PIM1 NFB stress response pathway and serves as a target for intervention to enhance the therapeutic effects of cytotoxic drugs such as docetaxel.

Received for publication, November 19, 2007 , and in revised form, April 18, 2008.

^* The work was supported by Department of Defense/CDMRP Prostate Cancer Program Award W81XWH-04-1-0087. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1S–5S.

¹ To whom correspondence should be addressed: Chao Family Comprehensive Cancer Center, Bldg. 56, Rm. 248, University of California, Irvine, 101 The City Dr., Orange, CA 92868. Tel.: 714-456-5153; Fax: 714-456-2242; E-mail: mlilly{at}uci.edu.

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