Activation of retinoic acid receptor reduces metastatic prostate cancer bone lesions through blocking endothelial-to-osteoblast transition
Activation of retinoic acid receptor reduces metastatic prostate cancer bone lesions through blocking endothelial-to-osteoblast transition
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.
Corn Paul G.、Shen Pengfei、Yu Guoyu、Song Jian H.、Lee Yu-Chen、Agarwal Sandeep K.、Panaretakis Theocharis、Yu-Lee Li-Yuan、Lin Sue-Hwa、Pacifici Maurizio、Pan Jing、Logothetis Christopher J.、Lin Song-Chang
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer CenterDepartment of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer CenterDepartment of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer CenterDepartment of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer CenterDepartment of Medicine, Section of Immunology Allergy & Rheumatology, Baylor College of MedicineDepartment of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer CenterDepartment of Medicine, Section of Immunology Allergy & Rheumatology, Baylor College of MedicineDepartment of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center||Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center||The University of Texas Graduate School of Biomedical Sciences at HoustonTranslational Research Program in Pediatric Orthopaedics, The Children?ˉs Hospital of PhiladelphiaDepartment of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer CenterDepartment of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center
肿瘤学基础医学分子生物学
Bone metastasisprostate cancertumor-induced boneEC-to-OSB conversionretinoic acid receptor agonists
Corn Paul G.,Shen Pengfei,Yu Guoyu,Song Jian H.,Lee Yu-Chen,Agarwal Sandeep K.,Panaretakis Theocharis,Yu-Lee Li-Yuan,Lin Sue-Hwa,Pacifici Maurizio,Pan Jing,Logothetis Christopher J.,Lin Song-Chang.Activation of retinoic acid receptor reduces metastatic prostate cancer bone lesions through blocking endothelial-to-osteoblast transition[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2021.12.22.473739.点此复制
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