Thulin Malin Hagberg, Ramberg Håkon, Nielsen Heidi Kristin, Grytli Helene Hartvedt, Sivanesan Shivanthe, Pandya Abhilash D, Seip Kotryna, Andressen Kjetil Wessel, Linder Anna, Øijordsbakken Miriam, Poutanen Matti, Katz Betina, Halvorsen Bente, Mælandsmo Gunhild Mari, Taskén Kristin Austlid
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Vita Stråket 11, 403 45, Gothenburg, Sweden.
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Nydalen, P.O. Box 4950, 0424, Oslo, Norway.
J Transl Med. 2025 Jun 17;23(1):672. doi: 10.1186/s12967-025-06644-7.
The therapeutic impact of beta-blockers (BB), beta-adrenergic receptor antagonists, on prostate cancer remains controversial. The underlying health conditions of BB users complicate the ability to isolate and evaluate the specific effects of these drugs on the tumour cells. This study investigated whether BBs, by inhibiting sympathetic nerve signalling, extended the duration of androgen deprivation therapy (ADT) effectiveness in patients with de novo metastatic hormone sensitive prostate cancer and in prostate cancer xenograft models, while also uncovering the molecular mechanisms involved.
An analysis was conducted on prospectively collected data from the Cancer Registry of Norway, Norwegian Prescription Database, and Norwegian Cause of Death Registry focusing on patients with de novo metastatic prostate cancer undergoing ADT using the commencement of second-line treatment as the endpoint. In addition, the causal effect of BB treatment was studied in two different hormone-sensitive prostate cancer xenograft mouse models. Prior to treatment, mice were surgically castrated, to mimic ADT, and tumour progression was tracked by measuring serum PSA levels. RNA sequencing was performed on xenografted orthotopic tumours to investigate the underlying mechanisms, utilizing annotation based on human data and protein levels were validated by the Protein Simple Immunoassay. Immune-related effects were evaluated using immunohistochemistry on tumour tissue and measuring neopterin levels, along with 92 analytes, using the OLINK proximity extension assay on serum samples from xenografted mice and prostate cancer patients, both BB users and non-users.
A competitive risk analysis indicated that BB treatment postponed the initiation of second-line treatment in prostate cancer patients on ADT. Additionally, in both prostate cancer xenograft models, BB treatment reduced tumour burden and delayed progression to castration-resistant prostate cancer. Mechanistically, BB treatment suppressed androgen receptor signalling and induced a metabolic shift by up-regulating oxidative phosphorylation transcripts and down-regulating those involved in fatty acid synthesis and the PI3K/AKT/mTOR pathway. Additionally, BB treatment increased serum pro-inflammatory cytokines, such as the IL23/IL17 axis, in both xenografted mice and in patient samples. Enhanced intra-tumoral CD68+ immune cell infiltration was also observed in the tumours.
The data suggest that BB combined with ADT delay the progression to castration-resistant prostate cancer. This may be achieved by influencing androgen receptor activity, adjusting energy metabolism and fostering a pro-inflammatory antitumoral microenvironment.
β受体阻滞剂（BB），即β肾上腺素能受体拮抗剂，对前列腺癌的治疗作用仍存在争议。BB使用者的潜在健康状况使得分离和评估这些药物对肿瘤细胞的特定作用变得复杂。本研究调查了BB是否通过抑制交感神经信号传导，延长了初发转移性激素敏感性前列腺癌患者和前列腺癌异种移植模型中雄激素剥夺治疗（ADT）的有效持续时间，同时还揭示了其中涉及的分子机制。
对挪威癌症登记处、挪威处方数据库和挪威死亡原因登记处前瞻性收集的数据进行分析，重点关注接受ADT的初发转移性前列腺癌患者，以二线治疗开始作为终点。此外，在两种不同的激素敏感性前列腺癌异种移植小鼠模型中研究了BB治疗的因果效应。在治疗前，对小鼠进行手术去势，以模拟ADT，并通过测量血清PSA水平跟踪肿瘤进展。对异种移植的原位肿瘤进行RNA测序以研究潜在机制，利用基于人类数据的注释，并通过蛋白质简单免疫测定法验证蛋白质水平。使用肿瘤组织免疫组化和测量新蝶呤水平评估免疫相关效应，同时使用OLINK邻位延伸测定法对来自异种移植小鼠和前列腺癌患者（包括BB使用者和非使用者）的血清样本中的92种分析物进行检测。
竞争性风险分析表明，BB治疗推迟了接受ADT的前列腺癌患者二线治疗的开始。此外，在两种前列腺癌异种移植模型中，BB治疗均减轻了肿瘤负担，并延迟了向去势抵抗性前列腺癌的进展。从机制上讲，BB治疗抑制了雄激素受体信号传导，并通过上调氧化磷酸化转录本和下调参与脂肪酸合成及PI3K/AKT/mTOR途径的转录本诱导了代谢转变。此外，BB治疗在异种移植小鼠和患者样本中均增加了血清促炎细胞因子，如IL23/IL17轴。在肿瘤中还观察到肿瘤内CD68+免疫细胞浸润增强。
数据表明，BB联合ADT可延迟向去势抵抗性前列腺癌的进展。这可能是通过影响雄激素受体活性、调整能量代谢和促进促炎性抗肿瘤微环境来实现的。
