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

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.

Pleckstrin homology (PH) domain and Leucine Rich Repeat Phosphatase 1 (Phlpp1) Suppresses Parathyroid Hormone Receptor 1 (Pth1r) Expression and Signaling During Bone Growth

“…A variety of transcription factors are known to bind to the Pth1r promoter and may be active in Phlpp‐inhibited chondrocytes. ( 68–72 ) Numerous potential transcription factor binding sites within the 2000‐bp H3K27ac enrichment peak in the Pth1r promoter were identified and are summarized in Supplementary Table S1. ( 73 ) One promising transcription factor, Ying Yang 1 (YY1), showed increased binding at the Pth1r promoter in response to Phlpp inhibition.…”

Second-generation hormonotherapy in prostate cancer and bone microenvironment

“…As we exposed previously, enzalutamide induced a TGFBR2 (TGF-β type II receptor) in osteoblast (Su et al 2019). TGFBR2 gene silencing promotes bone metastasis.…”

“…Mechanical strength in the axial skeleton was significantly reduced by enzalutamide (Wu et al 2016). Furthermore, enzalutamide significantly decreased TGFBR2 (TGF-β type II receptor) in osteoblasts both in vitro and in patients samples (Su et al 2019) TGFBR2 down-regulation was mediated by PTH1R via NR2F1 transcription factor (Su et al 2019). Furthermore, loss of TGFBR2 in osteoblasts significantly promoted Pca bone metastasis (Meng et al 2018).…”