Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in...

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Prostate cancer (CaP) bone metastasis is often dormant until later stages.
• Androgen deprivation alters androgen receptor (AR) coactivator expression, potentially driving progression to castration resistance.
• Coregulator disruptions may act as a molecular switch reactivating latent bone metastases.

Purpose of the Study:

• To investigate changes in AR-mediated transcription and coregulator recruitment in CaP cells co-cultured with bone-related cell lines.
• To understand the role of osteoblast (Saos-2) and monocyte (THP-1) activity in modulating AR signaling in CaP.
• To identify molecular mechanisms underlying CaP cell proliferation and AR transactivation within the bone marrow microenvironment.

Main Methods:

• Analyzed AR coregulator recruitment in androgen-sensitive (LNCaP) and resistant (C4-2) CaP cells co-cultured with Saos-2 and THP-1 cells.
• Assessed AR activity, expression, and coregulator complex dynamics (SRC1/TIF2, SMRT/NCoR) under varying androgen conditions.
• Performed global gene expression analysis to identify affected pathways.

Main Results:

• Androgen-resistant C4-2 cells showed higher AR expression and specific coregulator profiles (increased SRC1/TIF2, decreased SMRT/NCoR).
• Co-culture with Saos-2 or THP-1 significantly reduced AR activity (>90%) in both CaP cell types via coregulator dissociation.
• Cell proliferation responses varied: Saos-2 decreased, THP-1 increased LNCaP proliferation (androgen-absent); both decreased C4-2 proliferation (androgen-present/absent).

Conclusions:

• Bone marrow stroma cells (osteoblasts, monocytes) modulate AR activity in prostate cancer cells through cell-type-specific interactions.
• AR coregulator dynamics are crucial in regulating CaP cell proliferation and response to the bone microenvironment.
• Identified potential cell cycle and androgen-regulated genes involved in CaP progression within the bone marrow context.