Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan.
J Pineal Res. 2024 Oct;76(7):e70000. doi: 10.1111/jpi.70000.
Bone metastasis is the primary cause of death among patients with advanced prostate cancer (PCa). PCa tends to spread to bones and acquire the bone-like phenotype, causing osteoblastic bone metastasis. Unfortunately, there is no effective treatment for this condition. However, melatonin, which regulates our circadian rhythm, has been found to have anti-tumor properties. It has yet to be established whether it is effective in treating osteoblastic PCa metastasis. Our findings show that melatonin inhibits the production of endothelin-1 (ET-1) in osteoblastic PCa cells, suppressing osteoblast differentiation. Clinical results indicate that bone metastatic PCa patients have higher levels of ET-1 compared to nonmetastatic PCa patients. Furthermore, melatonin-induced miR-let-7f-5p inhibits ET-1-promoted osteoblast differentiation in osteoblastic PCa. Melatonin also suppresses the property of osteomimicry in osteoblastic PCa cells. Importantly, in the intratibia injection PCa metastasis model, melatonin decreased osteoblastic PCa tumor growth, inhibiting ET-1 production and osteoblast differentiation in vivo. Taken together, melatonin inhibits osteoblastic PCa-regulated osteoblastogenesis by reducing ET-1 production through upregulation of miR-let-7f-5p, while suppressing the property of osteomimicry in osteoblastic PCa. Melatonin therapy could be a promising approach to treating bone metastasis in osteoblastic PCa.
骨转移是晚期前列腺癌 (PCa) 患者死亡的主要原因。PCa 倾向于转移到骨骼并获得类似骨骼的表型，导致成骨骨转移。不幸的是，目前对此病症没有有效的治疗方法。然而，调节我们昼夜节律的褪黑素已被发现具有抗肿瘤特性。褪黑素是否能有效治疗成骨 PCa 转移尚未确定。我们的研究结果表明，褪黑素抑制成骨 PCa 细胞内皮素-1 (ET-1) 的产生，抑制成骨细胞分化。临床结果表明，骨转移 PCa 患者的 ET-1 水平高于非转移性 PCa 患者。此外，褪黑素诱导的 miR-let-7f-5p 抑制 ET-1 促进成骨 PCa 中的成骨细胞分化。褪黑素还抑制成骨 PCa 细胞中的成骨样模拟特性。重要的是，在胫骨内注射 PCa 转移模型中，褪黑素减少了成骨性 PCa 肿瘤的生长，通过上调 miR-let-7f-5p 抑制 ET-1 的产生和体内成骨细胞分化。总之，褪黑素通过上调 miR-let-7f-5p 减少 ET-1 的产生，抑制成骨性 PCa 调节的成骨细胞生成，同时抑制成骨 PCa 中的成骨样模拟特性。褪黑素治疗可能是治疗成骨性 PCa 骨转移的一种有前途的方法。
