Targeting HTR2B suppresses nonfunctioning pituitary adenoma growth and sensitizes cabergoline treatment via inhibiting Gαq/PLC/PKCγ/STAT3 axis.

IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY
Shaojian Lin, Liangbo Wang, Changxi Han, Yuting Dai, Changsheng Li, Yanting Liu, Bo Zhang, Ning Huang, Anke Zhang, Tao Zhang, Yu Wang, Jing Xie, Hao Tang, Yijun Cheng, Hong Yao, Meiqing Lou, Li Xue, Zhe Bao Wu
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Abstract

Background: Managing nonfunctioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline's (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential.

Methods: We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays.

Results: Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066.

Conclusions: HTR2B is a potential therapeutic target for NFPAs, and its inhibition could improve CAB efficacy. A dual therapy approach may be beneficial for NFPA patients with high HTR2B expression.

通过抑制 Gαq/PLC/PKCγ/STAT3 轴,靶向 HTR2B 可抑制非功能性垂体腺瘤的生长,并使卡麦角林治疗敏感化。
背景:由于药物治疗手段有限,治疗非功能性垂体腺瘤(NFPA)十分困难。卡麦角林(CAB)对无功能垂体腺瘤的疗效还存在争议。本研究探讨了 HTR2B 在 NFPA 中的作用及其治疗潜力:我们对大量 RNA 序列数据进行了筛选,以分析 HTR2B 在 NFPA 样本中的表达水平。我们进行了体外和体内实验,以评估调节 HTR2B 对肿瘤生长和细胞周期调控的影响。利用药理抑制剂和分子相互作用实验阐明了HTR2B介导的信号通路机制:结果:在 NFPA 样本中检测到 HTR2B 表达升高,这与肿瘤存活率增加有关。抑制 HTR2B 的活性可通过调节 G2M 细胞周期抑制肿瘤生长。研究发现,用 PRX-08066 抑制 HTR2B 可通过干扰 Gαq/PLC/PKC 通路阻断 STAT3 磷酸化和核转位。PKC-γ 和 STAT3 之间的直接相互作用对 STAT3 的活化至关重要。研究表明,CAB 会通过 HTR2B 激活 pSTAT3,从而降低其治疗潜力。然而,在表达 HTR2B 的垂体瘤细胞系、异种移植垂体瘤模型和患者来源样本中,HTR2B 拮抗剂与 CAB 的组合能显著抑制肿瘤细胞的增殖。对患者来源数据的分析表明,以HTR2B/PKC-γ上调和BTG2/GADD45A下调为特征的独特分子模式可能会从CAB和PRX-08066的联合治疗中获益:HTR2B是NFPA的潜在治疗靶点,抑制HTR2B可提高CAB的疗效。结论:HTR2B是NFPA的潜在治疗靶点,抑制HTR2B可提高CAB的疗效,双重治疗方法可能对HTR2B高表达的NFPA患者有益。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuro-oncology
Neuro-oncology 医学-临床神经学
CiteScore
27.20
自引率
6.30%
发文量
1434
审稿时长
3-8 weeks
期刊介绍: Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
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