Smets L A, Van den Berg J, Acton D, Top B, Van Rooij H, Verwijs-Janssen M
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam.
Blood. 1994 Sep 1;84(5):1613-9.
The present study investigates the relationship between mitochondrial activity and the expression of the BCL-2 gene in a panel of six human and murine leukemia/lymphoma cell lines. The cell lines all contained normal glucocorticoid receptors but differed widely in sensitivity to dexamethasone, ranging from very sensitive S49 lymphoma to completely resistant HL-60 acute leukemia cells. In this panel, 10- to 15-fold differences in basal adenosine triphosphate (ATP) content and adenosine diphosphate (ADP)/ATP ratio were correlated with up to fivefold differences in bcl-2 protein (in human cells) and approximately 25-fold difference in bcl-2 mRNA content (all cell lines). Moreover, ATP content and BCL-2 gene expression were inversely correlated with glucocorticoid sensitivity and cell cycle length. In resistant cell lines, sensitivity to dexamethasone was restored by the mitochondrial inhibitors rotenone and meta-iodobenzylguanidine. This sensitization was not accompanied by detectable reductions in bcl-2 mRNA or protein content, suggesting that the inhibitors were capable of overriding BCL-2-mediated inhibition of apoptosis. Increased mitochondrial activity and (overexpressed) BCL-2 appeared closely related properties of glucocorticoid-resistant cells, sharing common cellular targets in hormone-induced apoptosis.
本研究调查了六种人类和小鼠白血病/淋巴瘤细胞系中线粒体活性与BCL-2基因表达之间的关系。这些细胞系均含有正常的糖皮质激素受体，但对地塞米松的敏感性差异很大，从非常敏感的S49淋巴瘤到完全耐药的HL-60急性白血病细胞。在这个细胞系组中，基础三磷酸腺苷（ATP）含量和二磷酸腺苷（ADP）/ATP比值10至15倍的差异与bcl-2蛋白（在人类细胞中）高达五倍的差异以及bcl-2 mRNA含量（所有细胞系）约25倍的差异相关。此外，ATP含量和BCL-2基因表达与糖皮质激素敏感性和细胞周期长度呈负相关。在耐药细胞系中，线粒体抑制剂鱼藤酮和间碘苄胍可恢复对地塞米松的敏感性。这种致敏作用并未伴随着bcl-2 mRNA或蛋白含量的可检测降低，这表明抑制剂能够克服BCL-2介导的细胞凋亡抑制。线粒体活性增加和（过表达的）BCL-2似乎是糖皮质激素耐药细胞的密切相关特性，在激素诱导的细胞凋亡中具有共同的细胞靶点。
