{"doi":"10.1101/2021.12.22.473739","title":"Activation of retinoic acid receptor reduces metastatic prostate cancer bone lesions through blocking endothelial-to-osteoblast transition","abstract":"Abstract Metastatic prostate cancer (PCa) in bone induces bone-forming lesions that contribute to progression and therapy resistance. Currently strategies targeting PCa-induced bone formation are lacking. We previously showed that PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces PCa-induced bone formation. We found that palovarotene, a 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. RARα/β/γ isoform knockdown in 2H11 ECs blocked EC-to-OSB transition and osteoblast mineralization. Pan-RAR agonist ATRA inhibited MycCaP-BMP4-induced bone formation and tumor growth under castration. Furthermore, palovarotene or ATRA reduced plasma Tenascin C, a factor secreted by EC-OSB cells, which may be used to monitor treatment response. Mechanistically, BMP4-activated pSmad1 forms a complex with RAR in the nucleus of 2H11 cells. RAR activation by palovarotene or ATRA causes pSmad1 degradation by recruiting E3-ubiquitin ligase Smurf1 into the nuclear pSmad1/RARγ complex. Our findings suggest that palovarotene can be repurposed to target PCa-induced bone formation to improve clinical outcomes for bone metastasis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":219772,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":413097,"name":"Paul G. Corn","orcid":"0000-0002-4106-6335","position":1,"is_corresponding":false},{"id":744904,"name":"Pengfei Shen","orcid":"0000-0002-0370-0411","position":2,"is_corresponding":false},{"id":274888,"name":"Jian H. Song","orcid":"0000-0001-9252-1468","position":3,"is_corresponding":false},{"id":655649,"name":"Yu‐Chen Lee","orcid":"0000-0002-9510-3146","position":4,"is_corresponding":false},{"id":655650,"name":"Song-Chang Lin","orcid":"0000-0003-1763-1303","position":5,"is_corresponding":false},{"id":467632,"name":"Jing Pan","orcid":"0000-0002-9003-6781","position":7,"is_corresponding":false},{"id":819011,"name":"Sandeep K. Agarwal","orcid":"0000-0002-0053-2803","position":8,"is_corresponding":false},{"id":490398,"name":"Theocharis Panaretakis","orcid":"0000-0001-5754-6950","position":9,"is_corresponding":false},{"id":432877,"name":"Maurizio Pacifici","orcid":"0000-0001-6854-4942","position":10,"is_corresponding":false},{"id":70219,"name":"Christopher J. Logothetis","orcid":"0000-0002-6365-1711","position":11,"is_corresponding":false},{"id":744906,"name":"Li‐Yuan Yu‐Lee","orcid":"0000-0002-2353-406X","position":12,"is_corresponding":false},{"id":490397,"name":"Sue-Hwa Lin","orcid":"0000-0002-6122-4054","position":13,"is_corresponding":false},{"id":655651,"name":"Guoyu Yu","orcid":"0000-0003-3030-5983","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:53:42.928212Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}