Protein geranylgeranylation is critical for the regulation of survival and proliferation of lymphoma tumor cells.
Protein geranylgeranylation is critical for the regulation of survival and proliferation of lymphoma tumor cells.
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发表时间：
2003-11
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通讯作者：
Niels W.C.J. Van de Donk;D. Schotte;M. Kamphuis;A. V. van Marion;B. van Kessel;A. Bloem;H. Lokhorst
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作者：
Niels W.C.J. Van de Donk;D. Schotte;M. Kamphuis;A. V. van Marion;B. van Kessel;A. Bloem;H. Lokhorst
异戊烯基化是蛋白质膜定位和参与多种信号转导途径的必要条件。进行以下研究以检查蛋白质法尼基化和香叶基香叶基化对于调节淋巴瘤细胞存活和增殖的重要性。实验设计用β-羟基-β-甲基戊二酰-CoA还原酶抑制剂洛伐他汀处理淋巴瘤细胞，洛伐他汀通过消耗细胞内的法尼基焦磷酸和香叶基香叶基焦磷酸来抑制蛋白质法尼基化和香叶基香叶基化。此外，FTI-277和GGTI-298分别特异性抑制法尼基转移酶和香叶基香叶基转移酶活性。结果洛伐他汀仅抑制牛儿基牛儿基化可导致淋巴瘤细胞系和淋巴瘤患者纯化肿瘤细胞的细胞活力降低，并呈时间和剂量依赖性。细胞凋亡的诱导和增殖的抑制介导了活细胞数量的减少。此外，GGTI-298在诱导凋亡和抑制增殖方面比FTI-277更有效。抑制蛋白香叶基香叶基化诱导的细胞凋亡与Mcl-1蛋白水平的降低、线粒体跨膜电位的崩溃和caspase-3的激活有关。细胞增殖的抑制是由G（1）阻滞诱导所致。此外，低浓度的洛伐他汀使淋巴瘤细胞对地塞米松敏感，包括对这种药物耐药的细胞。结论蛋白质香叶基香叶基化对淋巴瘤细胞的存活和增殖具有重要的调节作用，洛伐他汀或香叶基香叶基转移酶抑制剂单独或与其他药物联合应用对淋巴瘤的治疗可能是有益的。
PURPOSE Prenylation is essential for membrane localization and participation of proteins in various signaling pathways. The following study was conducted to examine the importance of protein farnesylation and geranylgeranylation for the regulation of lymphoma cell survival and proliferation. EXPERIMENTAL DESIGN Lymphoma cells were treated with the beta-hydroxy-beta-methylglutaryl-CoA reductase inhibitor lovastatin, which inhibits protein farnesylation and geranylgeranylation by the depletion of intracellular pools of farnesylpyrophosphate and geranylgeranylpyrophosphate. In addition, farnesyl transferase and geranylgeranyl transferase activities were specifically inhibited by FTI-277 and GGTI-298, respectively. RESULTS Only inhibition of geranylgeranylation by lovastatin led to reduction of cell viability in lymphoma cell lines and purified tumor cells from lymphoma patients in a time- and dose-dependent way. Reduction in the number of viable cells was mediated by both induction of apoptosis and inhibition of proliferation. In addition, GGTI-298 was more effective in induction of apoptosis and inhibition of proliferation than FTI-277. Apoptosis induced by inhibition of protein geranylgeranylation was associated with a reduction of Mcl-1 protein levels, collapse of the mitochondrial transmembrane potential, and caspase-3 activation. Inhibition of proliferation resulted from the induction of G(1) arrest. Furthermore, lovastatin at low concentrations sensitized lymphoma cells to dexamethasone, including cells resistant to this drug. CONCLUSION These results indicate that protein geranylgeranylation is critical for the regulation of lymphoma tumor cell survival and proliferation and that pharmacological agents such as lovastatin or geranylgeranyl transferase inhibitors, alone or in combination with other drugs, may be useful in the treatment of lymphoma.