Protein Kinase Cα and Protein Kinase Cδ Play Opposite Roles in the Proliferation and Apoptosis of Glioma Cells
Protein Kinase Cα and Protein Kinase Cδ Play Opposite Roles in the Proliferation and Apoptosis of Glioma Cells
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发表时间：
2001-06
期刊：
影响因子：
11.2
通讯作者：
R. Mandil;E. Ashkenazi;M. Blass;I. Kronfeld;G. Kazimirsky;G. Rosenthal;F. Umansky;P. Lorenzo;P. Blumberg;C. Brodie
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作者：
R. Mandil;E. Ashkenazi;M. Blass;I. Kronfeld;G. Kazimirsky;G. Rosenthal;F. Umansky;P. Lorenzo;P. Blumberg;C. Brodie
蛋白激酶C（PKC）与胶质瘤的增殖和凋亡有关，但具体PKC亚型的作用仍不清楚。比较不同恶性程度的脑肿瘤，我们发现，恶性胶质瘤表达PKCα的水平较高，而PKCδ的水平较低，与低级别星形细胞瘤相比。与这些差异的机制作用一致，与对照组相比，PKCα在人U87胶质瘤细胞系中的过表达导致细胞增殖增强和胶质细胞酸性蛋白（GFAP）表达降低。PKCδ过表达抑制细胞增殖，增强GFAP表达。利用PKC嵌合体，我们发现PKCα和PKCδ的调节结构域介导了它们对细胞增殖和GFAP表达的影响。PKCα和PKC δ是细胞凋亡的潜在信号分子。因此，我们研究了这些亚型在胶质瘤细胞对凋亡刺激的抵抗中的作用。在U87细胞中，操纵PKCα水平对依托泊苷诱导的细胞凋亡几乎没有影响。相反，PKCδ的过表达使U87细胞对依托泊苷的凋亡作用更敏感，并且PKCδ在这些细胞中通过半胱天冬酶依赖性过程被切割。此外，表达内源性PKCδ的胶质瘤细胞系U373在依托泊苷的作用下发生凋亡，并且凋亡反应被PKCδ抑制剂rottlerin阻断。提示PKCα和PKCδ在胶质瘤细胞的增殖和凋亡中起相反的作用。
Protein kinase C (PKC) has been implicated in the proliferation and apoptosis of glial tumors, but the role of specific PKC isoforms remains unresolved. Comparing brain tumors differing in degree of malignancy, we found that malignant gliomas expressed higher levels of PKCα and lower levels of PKCδ as compared with low-grade astrocytomas. Consistent with a mechanistic role for these differences, overexpression of PKCα in the human U87 glioma cell line resulted in enhanced cell proliferation and decreased glial fibrillary acidic protein (GFAP) expression as compared with controls. Reciprocally, overexpression of PKCδ inhibited cell proliferation and enhanced GFAP expression. Using PKC chimeras, we found that the regulatory domains of PKCα and PKCδ mediated their effects on cell proliferation and GFAP expression. PKCα and δ have been implicated as potential signaling molecules in apoptosis. Therefore, we examined the role of these isoforms in the resistance of glioma cells to apoptotic stimuli. In U87 cells, manipulation of PKCα levels had little effect on apoptosis in response to etoposide. In contrast, overexpression of PKCδ rendered the U87 cells more sensitive to the apoptotic effect of etoposide, and PKCδ was cleaved in these cells by a caspase-dependent process. Furthermore, the glioma cell line U373, which expresses endogenous PKCδ, underwent apoptosis in response to etoposide, and the apoptotic response was blocked by the PKCδ inhibitor rottlerin. Our results suggest that PKCα and PKCδ play opposite roles in the proliferation and apoptosis of glioma cells.