Enzalutamide-induced and PTH1R-mediated TGFBR2 degradation in osteoblasts confers resistance in prostate cancer bone metastases.

Enzalutamide resistance has been observed in approximately 50% of patients with prostate cancer (PCa) bone metastases. Therefore, there is an urgent need to investigate the mechanisms and develop strategies to overcome resistance. We observed enzalutamide resistance in bone lesion development induced by PCa cells in mouse models. We found that the bone microenvironment was indispensable for enzalutamide resistance because enzalutamide significantly inhibited the growth of subcutaneous C4-2B tumors and the proliferation of C4-2B cells isolated from the bone lesions, and the resistance was recapitulated only when C4-2B cells were co-cultured with osteoblasts. In revealing how osteoblasts contribute to enzalutamide resistance, we found that enzalutamide decreased TGFBR2 protein expression in osteoblasts, which was supported by clinical data. This decrease was possibly through PTH1R-mediated endocytosis. We showed that PTH1R blockade rescued enzalutamide-mediated decrease in TGFBR2 levels and enzalutamide responses in C4-2B cells that were co-cultured with osteoblasts. This is the first study to reveal the contribution of the bone microenvironment to enzalutamide resistance and identify PTH1R as a feasible target to overcome the resistance in PCa bone metastases.

Cancer letters. 2021 Nov 06 [Epub ahead of print]

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

Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503, USA., Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503, USA; Inner Mongolia University, Hohhot, 010021, China., Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503, USA; University of Michigan, Ann Arbor, MI, 48109, USA., Anatomic/Clinical Pathology, Mayo Clinic, Rochester, MN, 55905, USA., Bioinformatics & Biostatistics Core, Van Andel Institute, Grand Rapids, MI, 49503, USA., Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA., Inner Mongolia University, Hohhot, 010021, China., Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, 49503, USA. Electronic address: .

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