Chemical Activation and Mechanical Sensitization of Piezo1 Enhance TRAIL-Mediated Apoptosis in Glioblastoma Cells.
Chemical Activation and Mechanical Sensitization of Piezo1 Enhance TRAIL-Mediated Apoptosis in Glioblastoma Cells.
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DOI：
10.1021/acsomega.3c00705
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发表时间：
2023-05-16
期刊：
影响因子：
4.1
通讯作者：
King, Michael R.
中科院分区：
文献类型：
--
作者：
Knoblauch, Samantha V.;Desai, Shanay H.;Dombroski, Jenna A.;Sarna, Nicole S.;Hope, Jacob M.;King, Michael R.
多形性胶质母细胞瘤（GBM）是最常见和最具侵袭性的原发性脑肿瘤，在标准治疗后的平均生存期不到15个月。如果受损的肿瘤细胞进行DNA修复或获得使转录因子p53失活的突变，使用目前的标准护理药物替莫唑胺（TMZ）治疗可能无效。肿瘤坏死因子相关凋亡诱导配体（Tumor necrosis factor-related apoptosis-inducing ligand， TRAIL）通过转录不依赖的机制，在多种肿瘤类型中触发细胞凋亡，同时避开健康细胞。GBM对TRAIL的抗性特别强，但研究发现，在静态条件下，机械受体Piezo1可以通过Yoda1激动剂激活，在其他癌细胞系中诱导TRAIL致敏。本研究通过Yoda1和流体剪切应力（FSS）刺激，探讨了Piezo1的化学和机械激活对trail介导的GBM细胞凋亡的影响和机制。本研究表明，与对照组相比，Yoda1 + TRAIL和FSS + TRAIL联合治疗显著增加了两种GBM细胞系的凋亡。此外，已知对TMZ具有抗性的细胞被发现具有更高水平的Piezo1表达，并且更容易受到Piezo1激活的TRAIL致敏。与低剂量和高剂量TMZ治疗相比，Yoda1 + TRAIL联合治疗显著降低了TMZ耐药GBM细胞的细胞活力。这项研究的结果表明，通过化学或机械激活Piezo1，使癌细胞对TRAIL治疗敏感，从而克服GBM中TMZ耐药性的高度特异性和微创方法的潜力。
Glioblastoma multiforme (GBM), the most common and aggressive type of primary brain tumor, has a mean survival of less than 15 months after standard treatment. Treatment with the current standard of care, temozolomide (TMZ), may be ineffective if damaged tumor cells undergo DNA repair or acquire mutations that inactivate transcription factor p53. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in multiple tumor types, while evading healthy cells, through a transcription-independent mechanism. GBM is particularly resistant to TRAIL, but studies have found that the mechanoreceptor Piezo1 can be activated under static conditions via Yoda1 agonist to induce TRAIL sensitization in other cancer cell lines. This study examines the effects and the mechanism of chemical and mechanical activation of Piezo1, via Yoda1 and fluid shear stress (FSS) stimulation, on TRAIL-mediated apoptosis in GBM cells. Here, we demonstrate that Yoda1 + TRAIL and FSS + TRAIL combination therapies significantly increase apoptosis in two GBM cell lines relative to controls. Further, cells known to be resistant to TMZ were found to have higher levels of Piezo1 expression and were more susceptible to TRAIL sensitization by Piezo1 activation. The combinatory Yoda1 + TRAIL treatment significantly decreased cell viability in TMZ-resistant GBM cells when compared to treatment with both low and high doses of TMZ. The results of this study suggest the potential of a highly specific and minimally invasive approach to overcome TMZ resistance in GBM by sensitizing cancer cells to TRAIL treatment via chemical or mechanical activation of Piezo1.
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影响因子：
3.8
作者：
Lee, Dae-Hee;Kim, Dong-Wook;Jung, Chang-Hwa;Lee, Yong J.;Park, Daeho
通讯作者：
Park, Daeho
影响因子：
6
作者：
Dombroski JA;Hope JM;Sarna NS;King MR
通讯作者：
King MR
影响因子：
4.4
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
5.7
作者：
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通讯作者：
King, Michael R.