TMZ‐induced PrPc/par‐4 interaction promotes the survival of human glioma cells
TMZ‐induced PrPc/par‐4 interaction promotes the survival of human glioma cells
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DOI：
10.1002/ijc.25985
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发表时间：
2012-01
影响因子：
6.4
通讯作者：
Dongxiao Zhuang;Yingchao Liu;Y. Mao;Liang Gao;Hai-shi Zhang;Shihai Luan;Feng-ping Huang;Qingquan Li
中科院分区：
文献类型：
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作者：
Dongxiao Zhuang;Yingchao Liu;Y. Mao;Liang Gao;Hai-shi Zhang;Shihai Luan;Feng-ping Huang;Qingquan Li
恶性胶质瘤即使在广泛的手术和化疗后也会复发。尽管一种相对新型的化疗药物替莫唑胺(TMZ)显示出了良好的抗胶质瘤活性，但其效果只持续了几个月，而且在许多情况下会产生耐药性。人们已经认识到，胶质瘤细胞对TMZ的反应是通过G2/M期阻滞，而不是细胞凋亡。在这里，我们证明了在TMZ治疗下，人脑胶质瘤细胞中由于细胞蛋白(PrPc)而产生的特定阶段的化疗耐药。TMZ诱导的G2/M期细胞株PrPc表达上调，且耐药能力增强，而G1/S期细胞PrPc表达水平降低，对细胞凋亡更为敏感。此外，对PrPc与PAR-4相关的生物学意义的研究首次证明了PrPc的内源性水平与胶质瘤细胞对TMZ的凋亡效应的抵抗力之间的关系。在TMZ处理后，PrPc通过抑制PKA介导的PAR-4磷酸化而发挥其抗凋亡活性，而PAR-4磷酸化对PAR-4的激活、核进入和启动细胞凋亡至关重要。在细胞周期依赖性化疗反应的背景下，这项研究的数据表明，利用PrPc依赖的途径来提高基于TMZ的方案对胶质瘤患者的疗效是可能的。
Malignant gliomas recur even after extensive surgery and chemo‐radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ), has demonstrated promising activity against gliomas, the effects last only a few months and drug resistance develops thereafter in many cases. It has been acknowledged that glioma cells respond to TMZ treatment by undergoing G2/M arrest, but not apoptosis. Here we demonstrate a phase‐specific chemotherapy resistance due to cellular prion protein (PrPc) in human glioma cells upon TMZ treatment. TMZ‐induced G2/M‐arrested cultures show an upregulation of PrPc expression and are more resistant, whereas G1/S‐phase cells that show decreased levels of PrPc are more sensitive to apoptosis. Furthermore, an investigation into the biological significance of PrPc association with par‐4 provided the first evidence of a relationship between the endogenous levels of PrPc and the resistance of glioma cells to the apoptotic effects of TMZ. Upon TMZ treatment, PrPc exerts its antiapoptotic activity by inhibiting PKA‐mediated par‐4 phosphorylation that are important for par‐4 activation, nuclear entry and initiation of apoptosis. In context with cell cycle‐dependent responses to chemotherapy, the data from this study suggest the possibility of exploiting the PrPc‐dependent pathway to improve the efficacy of TMZ‐based regimen for patients with gliomas.