Pharmacological Modulation of the Cytosolic Oscillator Affects Glioblastoma Cell Biology.

IF 3.6 4区 医学 Q3 CELL BIOLOGY Cellular and Molecular Neurobiology Pub Date : 2024-06-22 DOI:10.1007/s10571-024-01485-2
Paula M Wagner, Santiago J Fornasier, Mario E Guido
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Abstract

The circadian system is a conserved time-keeping machinery that regulates a wide range of processes such as sleep/wake, feeding/fasting, and activity/rest cycles to coordinate behavior and physiology. Circadian disruption can be a contributing factor in the development of metabolic diseases, inflammatory disorders, and higher risk of cancer. Glioblastoma (GBM) is a highly aggressive grade 4 brain tumor that is resistant to conventional therapies and has a poor prognosis after diagnosis, with a median survival of only 12-15 months. GBM cells kept in culture were shown to contain a functional circadian oscillator. In seeking more efficient therapies with lower side effects, we evaluated the pharmacological modulation of the circadian clock by targeting the cytosolic kinases glycogen synthase kinase-3 (GSK-3) and casein kinase 1 ε/δ (CK1ε/δ) with specific inhibitors (CHIR99021 and PF670462, respectively), the cryptochrome protein stabilizer (KL001), or circadian disruption after Per2 knockdown expression in GBM-derived cells. CHIR99021-treated cells had a significant effect on cell viability, clock protein expression, migration, and cell cycle distribution. Moreover, cultures exhibited higher levels of reactive oxygen species and alterations in lipid droplet content after GSK-3 inhibition compared to control cells. The combined treatment of CHIR99021 with temozolomide was found to improve the effect on cell viability compared to temozolomide therapy alone. Per2 disruption affected both GBM migration and cell cycle progression. Overall, our results suggest that pharmacological modulation or molecular clock disruption severely affects GBM cell biology.

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药理调节细胞震荡器影响胶质母细胞瘤细胞生物学
昼夜节律系统是一种保守的计时机制,可调节睡眠/觉醒、进食/禁食和活动/休息周期等一系列过程,从而协调行为和生理。昼夜节律紊乱是导致代谢性疾病、炎症性疾病和癌症风险增加的一个因素。胶质母细胞瘤(GBM)是一种侵袭性极强的四级脑肿瘤,对传统疗法具有抗药性,确诊后预后极差,中位生存期仅为 12-15 个月。研究表明,培养的 GBM 细胞含有功能性昼夜节律振荡器。为了寻求更有效、副作用更小的疗法,我们评估了药理学调控昼夜节律的方法,即用特异性抑制剂(分别为CHIR99021和PF670462)、隐色素蛋白稳定剂(KL001)靶向细胞膜激酶糖原合酶激酶-3(GSK-3)和酪蛋白激酶1ε/δ(CK1ε/δ),或在GBM衍生细胞中敲除Per2表达后破坏昼夜节律。经 CHIR99021 处理的细胞对细胞活力、时钟蛋白表达、迁移和细胞周期分布有显著影响。此外,与对照细胞相比,GSK-3 抑制后的培养物表现出更高水平的活性氧和脂滴含量的改变。与单独使用替莫唑胺治疗相比,CHIR99021与替莫唑胺联合治疗可提高对细胞活力的影响。破坏 Per2 会影响 GBM 迁移和细胞周期进展。总之,我们的研究结果表明,药理调节或分子钟破坏会严重影响 GBM 细胞生物学。
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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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