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PI3K 通路在胶质瘤细胞对替莫唑胺治疗的耐药中的作用。

Involvement of PI3K Pathway in Glioma Cell Resistance to Temozolomide Treatment.

机构信息

Department of Functional Anatomy and Cytobiology, Institute of Biological Sciences, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin, Poland.

Department of Medical Biology, Institute of Rural Health, Jaczewskiego 2, 20-950 Lublin, Poland.

出版信息

Int J Mol Sci. 2021 May 13;22(10):5155. doi: 10.3390/ijms22105155.

DOI:10.3390/ijms22105155
PMID:34068110
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8152763/
Abstract

The aim of the study was to investigate the anticancer potential of LY294002 (PI3K inhibitor) and temozolomide using glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cells. Apoptosis, autophagy, necrosis, and granules in the cytoplasm were identified microscopically (fluorescence and electron microscopes). The mitochondrial membrane potential was studied by flow cytometry. The activity of caspases 3, 8, and 9 and Akt was evaluated fluorometrically, while the expression of Beclin 1, PI3K, Akt, mTOR, caspase 12, and Hsp27 was determined by immunoblotting. SiRNA was used to block Hsp27 and PI3K expression. Cell migration and localization of Hsp27 were tested with the wound healing assay and immunocytochemistry, respectively. LY294002 effectively diminished the migratory potential and increased programmed death of T98G and MOGGCCM. Autophagy was dominant in MOGGCCM, while apoptosis was dominant in T98G. LY294002 with temozolomide did not potentiate cell death but redirected autophagy toward apoptosis, which was correlated with ER stress. A similar effect was observed after blocking PI3K expression with siRNA. Transfection with Hsp27 siRNA significantly increased apoptosis related to ER stress. Our results indicate that inhibition of the PI3K/Akt/mTOR pathway sensitizes glioma cells to apoptosis upon temozolomide treatment, which was correlated with ER stress. Hsp27 increases the resistance of glioma cells to cell death upon temozolomide treatment.

摘要

本研究旨在探讨 LY294002（PI3K 抑制剂）联合替莫唑胺对多形性胶质母细胞瘤（T98G）和间变性星形细胞瘤（MOGGCCM）细胞的抗癌作用。通过显微镜（荧光显微镜和电子显微镜）观察细胞凋亡、自噬、坏死和细胞质中的颗粒。通过流式细胞术研究线粒体膜电位。通过荧光法评估 caspase-3、8 和 9 以及 Akt 的活性，通过免疫印迹法评估 Beclin 1、PI3K、Akt、mTOR、caspase-12 和 Hsp27 的表达。使用 siRNA 阻断 Hsp27 和 PI3K 的表达。通过划痕愈合实验和免疫细胞化学法分别测试细胞迁移和 Hsp27 的定位。LY294002 有效降低了 T98G 和 MOGGCCM 的迁移潜力并增加了程序性细胞死亡。自噬在 MOGGCCM 中占主导地位，而凋亡在 T98G 中占主导地位。LY294002 联合替莫唑胺并未增强细胞死亡，但将自噬转向与内质网应激相关的凋亡。用 siRNA 阻断 PI3K 表达时观察到类似的效果。转染 Hsp27 siRNA 显著增加与内质网应激相关的凋亡。我们的研究结果表明，抑制 PI3K/Akt/mTOR 通路可增强替莫唑胺治疗时胶质母细胞瘤细胞对凋亡的敏感性，这与内质网应激有关。Hsp27 增加了胶质母细胞瘤细胞对替莫唑胺治疗的细胞死亡的抵抗力。

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