Adaptive and non-adaptive gene expression responses in prostate cancer during androgen deprivation.

Androgen deprivation therapy is the cornerstone treatment of advanced prostate cancer. Eventually prostate cancer cells overcome androgen deprivation therapy, giving rise to castration resistant prostate cancer (CRPC) characterized by increased androgen receptor (AR) activity. Understanding the cellular mechanisms leading to CRPC is needed for development of novel treatments. We used long-term cell cultures to model CRPC; a testosterone-dependent cell line (VCaP-T) and cell line adapted to grow in low testosterone (VCaP-CT). These were used to uncover persistent and adaptive responses to testosterone level. RNA was sequenced to study AR-regulated genes. Expression level changed due to testosterone depletion in 418 genes in VCaP-T (AR-associated genes). To evaluate significance for CRPC growth, we compared which of them were adaptive i.e., restored expression level in VCaP-CT. Adaptive genes were enriched to steroid metabolism, immune response and lipid metabolism. The Cancer Genome Atlas Prostate Adenocarcinoma data were used to assess the association with cancer aggressiveness and progression-free survival. Expressions of 47 AR-associated or association gaining genes were statistically significant markers for progression-free survival. These included genes related to immune response, adhesion and transport. Taken together, we identified and clinically validated multiple genes being linked with progression of prostate cancer and propose several novel risk genes. Possible use as biomarkers or therapeutic targets should be studied further.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Teemu J. Murtola has received lecture fees from Novartis, Janssen, Ferring, Sanofi and Bayer, and is a paid consultant for Novartis, Sanofi and Janssen. Teuvo L. J. Tammela is a paid consultant for Astellas, GSK, Pfizer, Orion Pharma and Amgen. The remaining authors declare no competing interests.
(Copyright: © 2023 Nätkin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)