Visit our Expo - Redox and Inflammation signaling 2012

Session XIV : Transcriptional and translational control Poster XIV, 21
Nemo-Like Kinase Inhibits Androgen Receptor Transcriptional Activity in Prostate
Cancer Cells
Katayoon H. Emami, Lisha G. Brown, Tiffany EM Pitts, and Eva Corey
GU Cancer Research Laboratory, Department of Urology, University of Washington,
Seattle, WA 98195, USA. Email: ecorey@u.washington.edu
Androgen receptor (AR) signaling and its interactions with other signaling pathways play
important roles in growth and differentiation of prostate and prostate cancer (CaP) cells.
Nemo-like kinase (NLK), a MAP kinase, has been reported to affect the activity of various
transcriptional factors via its interactions with co-activators #-catenin and CBP/p300. Because
MAP Kinases have been implicated in regulation of the AR signaling pathway and AR
signaling utilizes both #-catenin and CBP/p300 as coactivators, y we examined the effects of
NLK on AR signaling in CaP cells.
Our data show that inhibition of NLK expression by siRNA upregulates AR promoter
activity, while overexpression of NLK dramatically inhibits the activation of both an artificial
ARE and the PSA promoter in LNCaP prostate cancer cells. A kinase-dead NLK(K155M)
inhibited only ~50% of the AR transcriptional activity in LNCaP cells, implying that the
kinase activity of NLK is important for this inhibition but that other mechanisms are also
involved. Our data show that the mechanisms involved in the reduced transcriptional activity
of AR include disruption of interactions of AR with #-catenin and p300, decreased AR-DNA
binding, and alteration of the subcellular localization of AR. We undertook further studies to
investigate the biological effects associated with the inhibitory role of NLK in AR-directed
transcription and showed that NLK increases the rate of apoptosis in these cells.
Further studies of the roles of NLK in regulation of prostate cancer are warranted, since
understanding the molecular mechanism of regulation of AR transcriptional activity in CaP
cells is essential for identification of new targets to control this disease and may have a
dramatic impact on the therapeutic strategies adopted for the prevention and treatment of CaP.
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