Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

• Published in: Biochemical and biophysical research communications 2015-11, Vol.467 (4), p.1039-1045
• Main Authors: Villagran, Marcelo A., Gutierrez-Castro, Francisco A., Pantoja, Diego F., Alarcon, Jose C., Fariña, Macarena A., Amigo, Romina F., Muñoz-Godoy, Natalia A., Pinilla, Mabel G., Peña, Eduardo A., Gonzalez-Chavarria, Ivan, Toledo, Jorge R., Rivas, Coralia I., Vera, Juan C., McNerney, Eileen M., Onate, Sergio A.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ANDROGENS; Androgens - physiology; Bone and Bones - metabolism; Bone and Bones - pathology; BONE MARROW; Bone stroma; CASTRATION; CELL CYCLE; Cell Line, Tumor; CELL PROLIFERATION; CONNECTIVE TISSUE CELLS; GENES; Humans; LIGANDS; Male; METASTASES; MONOCYTES; OSTEOSARCOMAS; PROSTATE; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - pathology; RECEPTORS; Receptors, Androgen - metabolism; SKELETON; THERAPY; TRANSCRIPTION
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.10.009

Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. •Decreased corepressor expression change AR in androgen-resistance prostate cancer.•Bone stroma-derived cells change AR coregulator recruitment in prostate cancer.•Bone stroma cells change cell proliferation in androgen-resistant cancer cells.•Global gene expression in CaP cells is modified by bone stroma cells in co-cultures.•Potential new multi-subunit coactivator complexes for AR in CaP bone metastasis.