Abstract
\#946;2-Microglobulin (\#946;2M) is a critical promoter of osteomimicry and cell proliferation in human prostate cancer cells through a cAMP/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signaling pathway (Huang et al., Cancer Res., 65:2303-13, 2005). Blockade of \#946;2M and its related signaling axis using a new agent, anti-\#946;2M monoclonal antibody (\#946;2M mAb), inhibited mRNA and protein expression of androgen receptor (AR) and its target gene, prostate-specific antigen (PSA), in prostate cancer cells and induced programmed death of prostate cancer cells by activating a caspase-9 dependent pathway, in vitro and in vivo. The molecular mechanism by which \#946;2M mAb inhibited AR expression was through decreasing the interaction between a lipogenic transcription factor, sterol regulatory element-binding protein-1 (SREBP-1), and its binding cis-acting element located in the 5\#8217;-flanking AR promoter region, as determined by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). The functional study of SREBP-1 revealed that knocking down or overexpressing SREBP-1 using sequence-specific siRNA or an expression vector decreased or increased total and nuclear AR proteins and cell viability in prostate cancer cells. SREBP-1 has been identified and reported as a key regulator of genes involved in fatty acid and cholesterol biosynthesis. Inhibiting AR expression by \#946;2M mAb also significantly decreased SREBP-1 expression and fatty acid contents in prostate cancer cells, which are important for cell membrane construction and energy storage. In summary, \#946;2M mAb may be a potent and attractive pleiotropic therapeutic agent that can inhibit AR expression, lipid metabolism, cell proliferation and survival in prostate cancer cells through down-regulation of a lipogenic pathway.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 849.
Footnotes
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
- American Association for Cancer Research