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.
Cancer Lett. 2022 Jan 28;525:170-178. doi: 10.1016/j.canlet.2021.10.042. Epub 2021 Nov 6.
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.
恩扎卢胺耐药已在约 50%的前列腺癌（PCa）骨转移患者中观察到。因此，迫切需要研究机制并制定策略来克服耐药性。我们在小鼠模型中观察到骨病变发展中恩扎卢胺耐药。我们发现骨微环境对于恩扎卢胺耐药是必不可少的，因为恩扎卢胺显著抑制了皮下 C4-2B 肿瘤的生长和骨病变中分离的 C4-2B 细胞的增殖，并且只有当 C4-2B 细胞与成骨细胞共培养时才会重现耐药性。在揭示成骨细胞如何促成恩扎卢胺耐药性时，我们发现恩扎卢胺降低了成骨细胞中 TGFBR2 蛋白的表达，这一发现得到了临床数据的支持。这种减少可能是通过 PTH1R 介导的内吞作用。我们表明，PTH1R 阻断可挽救与成骨细胞共培养的 C4-2B 细胞中恩扎卢胺介导的 TGFBR2 水平降低和恩扎卢胺反应。这是第一项揭示骨微环境对恩扎卢胺耐药性的贡献并确定 PTH1R 作为克服 PCa 骨转移耐药性的可行靶点的研究。
