UroToday - Androgen Receptor Decoy Molecules Block the Growth of Prostate Cancer

December 2, 2008

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Androgen Receptor Decoy Molecules Block the Growth of Prostate Cancer

Monday, 26 February 2007

BERKELEY, CA (UroToday.com) - The androgen receptor (AR) is central to activation of androgen-regulated genes (such as PSA) in both androgen sensitive and androgen insensitive prostate cancer (CaP).

Functional domains in AR include a C-terminal ligand-binding domain (LBD), a DNA-binding domain and an N-terminal domain (NTD). Androgen binds to the LBD, translocates to the nucleus and complexes to androgen-response elements (AREs), which activates gene transcription. In the absence of androgen, other factors such as growth factors can activate the NTD to complex with AREs and induce gene transcription. Dr. Sadar and research colleagues created decoy NTD molecules and found that expression of the decoy molecules in CaP cells competitively bound to interacting proteins and decreased CaP growth in laboratory and animal models. Their report appears in the January 23, 2007 issue of the Proceedings of the National Academy of Science.

A construct encoding amino acids 1-558 of the AR NTD was transfected into LNCaP androgen sensitive CaP cells. It was expressed by the cells and upon addition of growth factors decreased PSA expression by 66%. This would be due to the decoy AR NTD competitively binding the growth factor, leaving little to bind to the NTD of the cells' native AR. LNCaP cells expressing the decoy NTD were implanted in intact (non-castrate) mice and while controls developed tumors in 100% of mice, the decoy mice had a tumor take rate of only 58%. Expression of PSA occurred at 5 weeks in controls as compared to 9 weeks in decoy mice and control mice had PSA levels ten times higher at the conclusion of the experiment. Tumor volume was four times larger in the control animals.

In castrated mice, the time to androgen-independence was evaluated. Castration resulted in a >90% decrease in serum PSA in all mice by 4 weeks. PSA began to rapidly rise in control mice, while the decoy group PSA remained less than 20% of the pre-castrate level throughout the duration of the experiment. Immunhistochemical staining of tumors for proliferation showed decreased proliferation in the decoy tumors. Apoptotic cell death was measured by TUNEL staining and showed that reduced decoy tumor growth was due to increased cell death in addition to decreased proliferation.

The use of decoy AR NTD inhibited androgen-dependent and androgen-independent expression of PSA and tumor growth. This innovative work models a strategy to treat androgen-independent CaP.

Steven N. Quayle, Nasrin R. Mawji, Jun Wang, and Marianne D. Sadar

PNAS 2007;104:1331-6.

UroToday.com Prostate Cancer Section