HTR1D regulates the PI3K/Akt signaling pathway to impact glioblastoma development and resistance to temozolomide

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Huanqi Zhang , Ziyan Liu , Jing Cheng , Yiming Jiang , Xiaoli Zheng , Chong Zhang , Yangling Li
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Abstract

Glioblastoma (GBM), the most aggressive primary brain tumor, presents significant therapeutic challenges owing to limited treatment options beyond the cornerstone chemotherapy temozolomide (TMZ) and its intrinsic chemoresistance. This study elucidates additional mechanisms of the multimodal antidepressant vortioxetine in GBM, extending beyond the reported PI3K/Akt pathway modulation. RNA-sequencing analysis identified five potential vortioxetine-responsive targets in GBM cells: SCN5A, HTR1D, SLC6A9, KIF11, and ADRB2. Notably, only HTR1D overexpression correlated with poor disease-free survival in GBM patients. Vortioxetine-mediated HTR1D suppression suggests its potential role as an HTR1D inhibitor in GBM progression. HTR1D-overexpressing GBM cells exhibited enhanced proliferative and migratory capacities. LinkedOmics database analysis revealed the HTR1D regulation on PI3K/Akt axis, a dominant signaling pathway showing significant positive correlation with TMZ resistance. Crucially, HTR1D knockdown enhanced TMZ sensitivity in GBM cells. Moreover, the TMZ-vortioxetine combination demonstrated marked synergistic anti-tumor effects concomitant with HTR1D suppression. In vivo, the TMZ-vortioxetine combination more effectively suppressed GBM proliferation than either agent alone. Collectively, these findings identify HTR1D as a novel vortioxetine target in GBM that modulates proliferation, metastasis, and TMZ resistance via PI3K/Akt signaling. This study provides convincing preclinical evidence for TMZ-vortioxetine combination therapy, proposing both a new therapeutic target and a viable strategy to circumvent TMZ resistance in GBM.
HTR1D调节PI3K/Akt信号通路,影响胶质母细胞瘤的发展和对替莫唑胺的耐药性。
胶质母细胞瘤(GBM)是最具侵袭性的原发性脑肿瘤,由于基础化疗替莫唑胺(TMZ)及其固有的化疗耐药之外的治疗选择有限,给治疗带来了重大挑战。本研究阐明了多模式抗抑郁药vortioxetine在GBM中的其他机制,超出了报道的PI3K/Akt通路调节。rna测序分析确定了GBM细胞中五个潜在的vortioxetine应答靶点:SCN5A、HTR1D、SLC6A9、KIF11和ADRB2。值得注意的是,在GBM患者中,只有HTR1D过表达与较差的无病生存率相关。vortioxetine介导的HTR1D抑制提示其在GBM进展中作为HTR1D抑制剂的潜在作用。过表达htr1d的GBM细胞表现出增强的增殖和迁移能力。LinkedOmics数据库分析显示,HTR1D调控PI3K/Akt轴,这是一个与TMZ抗性显著正相关的显性信号通路。关键是,HTR1D敲除增强了GBM细胞的TMZ敏感性。此外,TMZ-vortioxetine联合用药显示出显著的协同抗肿瘤作用,同时抑制HTR1D。在体内,TMZ-vortioxetine联合使用比单独使用任何一种药物更有效地抑制GBM增殖。总之,这些发现表明HTR1D是GBM中vortioxetine的新靶点,通过PI3K/Akt信号调节增殖、转移和TMZ耐药性。本研究为TMZ-vortioxetine联合治疗GBM提供了令人信服的临床前证据,提出了新的治疗靶点和可行的策略来规避TMZ耐药。
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来源期刊
CiteScore
7.70
自引率
3.90%
发文量
410
审稿时长
36 days
期刊介绍: Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.
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