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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
models of human malignancies including prostate cancers. It was
previously shown that bombesin and/or neurotensin (NT) acts as a
survival and 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
investigate the biological effects and signal pathways of bombesin and
NT on LNCaP, a prostate cancer cell line which requires androgen for
growth. We show that both neurotrophic factors can induce LNCaP growth
in the absence of androgen. Concurrent transactivation of reporter
genes driven by the prostate-specific antigen promoter or a promoter
carrying an androgen-responsive element (ARE) indicate that growth
stimulation is accompanied by androgen receptor (AR) activation.
Furthermore, neurotrophic factor-induced gene activation was also
present in PC3 cells transfected with the AR but not in the parental
line which lacks the AR. Given that bombesin does not directly bind to
the AR and is known to engage a G-protein-coupled receptor, we
investigated downstream signaling events that could possibly interact
with the AR pathway. We found that three nonreceptor tyrosine kinases,
focal adhesion kinase (FAK), Src, and Etk/BMX play important parts in
this process. Etk/Bmx activation requires FAK and Src and is critical
for neurotrophic factor-induced growth, as LNCaP cells transfected with
a dominant-negative Etk/BMX fail to respond to bombesin. Etk's
activation requires FAK, Src, but not phosphatidylinositol 3-kinase.
Likewise, bombesin-induced AR activation is inhibited by the
dominant-negative mutant of either Src or FAK. Thus, in addition to
defining a new G-protein pathway, this report makes the following
points regarding prostate cancer. (i) Neurotrophic factors can activate
the AR, thus circumventing the normal growth inhibition caused by
androgen ablation. (ii) Tyrosine kinases are involved in neurotrophic
factor-mediated AR activation and, as such, may serve as targets of
future therapeutics, to be used in conjunction with current antihormone
and antineuropeptide therapies.
*
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.
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.
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