Endocrine Abstracts

Androgen receptor (AR) signaling is critical at all stages of prostate cancer including chemically castrated late-stage forms of the disease. How the AR can initiate transcription in the absence of androgens has been proposed to occur through several mechanisms including the production of constitutively active androgen receptor variants. Lacking a ligand binding domain, these variants are intrinsically resistant to all clinically approved AR antagonists and have been found to correlate to drug resistance. Yet many fundamental questions still remain about their mechanism of action. Given the proposed clinical importance, a better understanding of ARV7 activation is critical to treating late-stage prostate cancer patients. Surprisingly, in LNCaP single cell colonies expressing a tetracycline-inducible ARV7 we found that overexpression of the variant rapidly causes marked cellular senescence and the degree of senescence was dependent on the level of expression. Senescence was independent of full-length AR and was mediated by AR transcriptional activity. ARV7 was found to induce senescence via ROS production which leads to the activation of the p53 pathway. Demonstrating that this phenotype was not limited to LNCaP cells, we observed a similar senescence in several androgen responsive prostate cancer cell lines. Interestingly, we were able to identify several LNCaP clones that were resistant to expression of ARV7. Overall our results demonstrate that constitutive activity of ARV7 is not tolerated in AR dependent cells and may represent a “barrier” for the cancer to overcome.

Funding: TÜBİTAK 1001-114Z491 and 3501-113Z382 grants.

Presenting Author: Nathan A. Lack, Koç University, School of Medicine, Istanbul, Turkey. Email: [email protected]