Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 43, Issue 4, Pages 594-603Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2010.12.017
Keywords
Bad; Bcl-xL; LY294002; Pim-1; Prostate cancer
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Funding
- National Medical Research Council, Singapore [NMRC/1077/2006]
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The present report investigated the pathway(s) involved in the inhibition of apoptosis by the synthetic androgen, R1881 in serum-starved LNCaP cells exposed to the pi3K inhibitor, LY294002. R1881 blocked LY294002-induced apoptosis through the inhibition of Bak activation via an increase in Bcl-xL transcription and protein expression. In addition, R1881 treatment enhanced the stability of the Pim-1 kinase, resulting in the inhibition of the activation of the BH3-only protein Bad through its phosphorylation at ser75. Pharmacological inhibition of the Pim-1 kinase activity with quercetagetin, a highly selective Pim-1 inhibitor, prevented R1881-mediated increase in Bad phosphorylation and restored cell sensitivity to LY294002-induced apoptosis despite the increase in Bcl-xL expression. These results demonstrate for the first time that the inhibition of LY294002-induced apoptosis by androgen is a function of an androgen receptor-dependent genomic signaling pathway leading to an increase in Bcl-xL expression as well as a non-genomic, Pim-1-dependent, signaling pathway mediated via phosphorylation of Bad at ser75. (C) 2010 Elsevier Ltd. All rights reserved.
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