Neuropeptide-Induced Androgen Independence in Prostate Cancer Cells: Roles of Nonreceptor Tyrosine Kinases Etk/Bmx, Src, and Focal Adhesion Kinase

doi:10.1128/MCB.21.24.8385-8397.2001

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Molecular and Cellular Biology, December 2001, p. 8385-8397, Vol. 21, No. 24
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.24.8385-8397.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Neuropeptide-Induced Androgen Independence in Prostate Cancer Cells: Roles of Nonreceptor Tyrosine Kinases Etk/Bmx, Src, and Focal Adhesion Kinase

Li-Fen Lee,¹ Junlin Guan,² Yun Qiu,³ and Hsing-Jien Kung^*

Department of Biological Chemistry and Cancer Center, University of California at Davis, Sacramento, California 958171¹; Cancer Biology Laboratories, Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853²; and Department of Laboratory Medicine and Pathology and Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455³

Received 26 March 2001/Returned for modification 22 May 2001/Accepted 6 September 2001

The bombesin/gastrin-releasing peptide (GRP) family of neuropeptides has been implicated in various in vitro and in vivo modelsof human malignancies including prostate cancers. It was previouslyshown that bombesin and/or neurotensin (NT) acts as a survivaland migratory factor(s) for androgen-independent prostate cancers.However, a role in the transition from an androgen-dependent to-refractory state has not been addressed. In this study, we investigatethe biological effects and signal pathways of bombesin and NTon LNCaP, a prostate cancer cell line which requires androgenfor growth. We show that both neurotrophic factors can induceLNCaP growth in the absence of androgen. Concurrent transactivationof reporter genes driven by the prostate-specific antigen promoteror a promoter carrying an androgen-responsive element (ARE) indicatethat growth stimulation is accompanied by androgen receptor (AR)activation. Furthermore, neurotrophic factor-induced gene activationwas also present in PC3 cells transfected with the AR but notin the parental line which lacks the AR. Given that bombesin doesnot directly bind to the AR and is known to engage a G-protein-coupledreceptor, we investigated downstream signaling events that couldpossibly interact with the AR pathway. We found that three nonreceptortyrosine kinases, focal adhesion kinase (FAK), Src, and Etk/BMXplay important parts in this process. Etk/Bmx activation requiresFAK and Src and is critical for neurotrophic factor-induced growth,as LNCaP cells transfected with a dominant-negative Etk/BMX failto respond to bombesin. Etk's activation requires FAK, Src, butnot phosphatidylinositol 3-kinase. Likewise, bombesin-inducedAR activation is inhibited by the dominant-negative mutant ofeither Src or FAK. Thus, in addition to defining a new G-proteinpathway, this report makes the following points regarding prostatecancer. (i) Neurotrophic factors can activate the AR, thus circumventingthe normal growth inhibition caused by androgen ablation. (ii)Tyrosine kinases are involved in neurotrophic factor-mediatedAR activation and, as such, may serve as targets of future therapeutics,to be used in conjunction with current antihormone and antineuropeptidetherapies.

^* Corresponding author. Mailing address: UC Davis Cancer Center, Res. III, UCDMC, 4645 2nd Ave., Sacramento, CA 95817. Phone:(916) 734-1538. Fax: (916) 734-2589. E-mail: hkung{at}ucdavis.edu.

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