Retinoic Acid Receptor Activation Reduces Metastatic Prostate Cancer Bone Lesions by Blocking the Endothelial-to-Osteoblast Transition

Authors

Guoyu Yu
Paul G Corn
Pengfei Shen
Jian H Song
Yu-Chen Lee
Song-Chang Lin
Jing Pan
Sandeep K Agarwal
Theocharis Panaretakis
Maurizio Pacifici
Christopher J Logothetis
Li-Yuan Yu-Lee
Sue-Hwa Lin

Publication Date

9-2-2022

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-22-0170

PMID

35802768

PMCID

PMC9444986

PubMedCentral® Posted Date

3-2-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Bone Neoplasms, Endothelial Cells, Humans, Male, Osteoblasts, Prostatic Neoplasms, Receptors, Retinoic Acid, Tretinoin, Ubiquitin-Protein Ligases, Bone metastasis, prostate cancer, tumor-induced bone, EC-to-OSB transition, retinoic acid receptor agonists

Abstract

Metastatic prostate cancer (PCa) in the bone induces bone-forming lesions that contribute to progression and therapy resistance. PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Current strategies targeting PCa-induced bone formation are lacking. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces PCa-induced bone formation. Treatment with palovarotene, an RARγ agonist being tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited EC-to-OSB transition and osteoblast mineralization in vitro and decreased tumor-induced bone formation and tumor growth in several osteogenic PCa models, and similar effects were observed with the pan-RAR agonist ATRA. Knockdown of RARα, β, or γ isoforms in ECs blocked BMP4-induced EC-to-OSB transition and osteoblast mineralization, indicating a role for all three isoforms in PCa-induced bone formation. Furthermore, treatment with palovarotene or ATRA reduced plasma Tenascin C, a factor secreted from EC-OSB cells, which may be used to monitor treatment response. Mechanistically, BMP4-activated pSmad1 formed a complex with RAR in the nucleus of ECs to activate EC-to-OSB transition. RAR activation by palovarotene or ATRA caused pSmad1 degradation by recruiting the E3-ubiquitin ligase Smurf1 to the nuclear pSmad1/RARγ complex, thus blocking EC-to-OSB transition. Collectively, these findings suggest that palovarotene can be repurposed to target PCa-induced bone formation to improve clinical outcomes for patients with bone metastasis.

Comments

Associated Data