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Enzalutamide-induced PTH1R-mediated TGFBR2 decrease in osteoblasts contributes to resistance in prostate cancer bone metastases

View ORCID ProfileShang Su, Jingchen Cao, Xiangqi Meng, Ruihua Liu, Alexandra Vander Ark, Erica Woodford, Reian Zhang, Isabelle Stiver, Xiaotun Zhang, Zachary B. Madaj, Megan J. Bowman, View ORCID ProfileYingying Wu, View ORCID ProfileH. Eric Xu, Bin Chen, Haiquan Yu, Xiaohong Li
doi: https://doi.org/10.1101/829044
Shang Su
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
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  • ORCID record for Shang Su
Jingchen Cao
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
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Xiangqi Meng
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
2The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China
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Ruihua Liu
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
3Inner Mongolia University, Hohhot, 010021, China
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Alexandra Vander Ark
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
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Erica Woodford
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
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Reian Zhang
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
4University of Michigan, Ann Arbor, MI, 48109
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Isabelle Stiver
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
4University of Michigan, Ann Arbor, MI, 48109
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Xiaotun Zhang
5Anatomic/Clinical Pathology, Mayo Clinic, Rochester, MN, 55905
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Zachary B. Madaj
6Bioinformatics & Biostatistics Core, Van Andel Institute, Grand Rapids, MI, 49503
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Megan J. Bowman
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
7Ball Horticultural Company, West Chicago, IL, 60185
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Yingying Wu
8Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503
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H. Eric Xu
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
9Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
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Bin Chen
8Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503
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Haiquan Yu
3Inner Mongolia University, Hohhot, 010021, China
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Xiaohong Li
1Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503
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  • For correspondence: xiaohong.li@vai.org
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Abstract

Over 80% of prostate cancer (PCa) patients in the United States die with bone metastases. Second-line hormonal therapies, such as enzalutamide, improve overall survival in about 50% of patients with bone metastases, but almost all responsive patients eventually develop enzalutamide resistance. Our study showed that although enzalutamide significantly inhibited the tumor growth of subcutaneously or orthotopically grafted PCa C4-2B cells, it had no effect on the bone lesion development when C4-2B tumors were grafted in the bone, suggesting a crucial role of the microenvironment in enzalutamide resistance in PCa bone metastasis. We found that enzalutamide significantly decreased the amount of the TGFBR2 (TGF-β type II receptor) in osteoblasts, both in vitro and in patient samples. The osteoblast-specific knockout of Tgfbr2 significantly induced bone metastasis. We showed that the enzalutamide-induced TGFBR2 decrease in osteoblasts was mediated by increased PTH1R (parathyroid hormone/parathyroid hormone-related peptide receptor), which resulted in TGFBR2 degradation, and that blocking PTH1R rescued the TGFBR2 decrease. Furthermore, we found that PTH1R up-regulation by enzalutamide was correlated with increased Pth1r promoter occupancy by transcription factor NR2F1. Our findings highlight a potential enzalutamide-resistance mechanism through TGFBR2 decrease in osteoblasts, thus suggesting future PTH1R-blocking approaches to overcome enzalutamide resistance in PCa bone metastasis.

Footnotes

  • Financial support: This work was supported by R01CA230744.

  • Conflict of Interest Disclosure: The authors have declared that no conflicts of interest exist.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 25, 2019.
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Enzalutamide-induced PTH1R-mediated TGFBR2 decrease in osteoblasts contributes to resistance in prostate cancer bone metastases
Shang Su, Jingchen Cao, Xiangqi Meng, Ruihua Liu, Alexandra Vander Ark, Erica Woodford, Reian Zhang, Isabelle Stiver, Xiaotun Zhang, Zachary B. Madaj, Megan J. Bowman, Yingying Wu, H. Eric Xu, Bin Chen, Haiquan Yu, Xiaohong Li
bioRxiv 829044; doi: https://doi.org/10.1101/829044
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Enzalutamide-induced PTH1R-mediated TGFBR2 decrease in osteoblasts contributes to resistance in prostate cancer bone metastases
Shang Su, Jingchen Cao, Xiangqi Meng, Ruihua Liu, Alexandra Vander Ark, Erica Woodford, Reian Zhang, Isabelle Stiver, Xiaotun Zhang, Zachary B. Madaj, Megan J. Bowman, Yingying Wu, H. Eric Xu, Bin Chen, Haiquan Yu, Xiaohong Li
bioRxiv 829044; doi: https://doi.org/10.1101/829044

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