Kanatani Y, Kasukabe T, Okabe-Kado J, Hayashi S, Yamamoto-Yamaguchi Y, Motoyoshi K, Nagata N, Honma Y
Department of Chemotherapy, Saitama Cancer Center Research Institute, Japan.
Cell Growth Differ. 1996 Feb;7(2):187-96.
Glucocorticoids inhibit the proliferation of lymphoid leukemia cells, whereas most myeloid leukemia cells are resistant to glucocorticoids. However, this study showed that glucocorticoids significantly and preferentially inhibited growth of monocytoid leukemia cells in combination with a low concentration of transforming growth factor beta (TGF beta). Combined 1 alpha,25-dihydroxyvitamin D3 and TGF beta markedly induced monocytic differentiation of U937 cells, whereas dexamethasone (Dex) and TGF beta essentially did not, although both combinations similarly inhibited the growth of U937 cells. The growth inhibition was accompanied by a block in the cell cycle progression from G1 to S phase (G1 arrest). Expression of glucocorticoid receptors was not affected by TGF beta, although they are induced during the monocytic differentiation of myelogenous leukemia cells and have increased sensitivity to glucocorticoids. The expression of TGF beta receptors also was not enhanced by Dex. TGF beta significantly stimulated glucocorticoid responsive element-mediated transcription activity. Combined Dex and TGF beta stimulated the expression of c-jun and c-fos early responsive genes in U937 cells, although Dex or TGF beta alone did not. The combination synergistically induced expression of c-jun gene, reaching a maximum level at 24 h. On the other hand, expression of c-fos gene was induced by TGF beta alone and increased additively in combination with Dex. Treatment with antisense oligonucleotide complementary to the first exon of c-jun mRNA reduced the growth-inhibitory effect of Dex and TGF beta in a dose-dependent manner. However, exposure of U937 cells to the sense oligomer of c-jun mRNA or an antisense oligomer of c-fos mRNA did not affect the growth inhibition. These results suggested that the preferential expression of c-jun and stimulation of glucocorticoid responsive element-mediated transactivation are closely associated with the growth arrest of U937 cells incubated with Dex and TGF beta.
糖皮质激素可抑制淋巴白血病细胞的增殖，而大多数髓系白血病细胞对糖皮质激素具有抗性。然而，本研究表明，糖皮质激素与低浓度的转化生长因子β（TGF-β）联合使用时，可显著且优先抑制单核细胞样白血病细胞的生长。1α,25-二羟基维生素D3与TGF-β联合使用可显著诱导U937细胞的单核细胞分化，而地塞米松（Dex）与TGF-β联合使用则基本无此作用，尽管两种组合均同样抑制U937细胞的生长。生长抑制伴随着细胞周期从G1期向S期进展的阻滞（G1期停滞）。糖皮质激素受体的表达不受TGF-β的影响，尽管它们在髓性白血病细胞的单核细胞分化过程中被诱导，且对糖皮质激素的敏感性增加。Dex也未增强TGF-β受体的表达。TGF-β可显著刺激糖皮质激素反应元件介导的转录活性。Dex与TGF-β联合使用可刺激U937细胞中c-jun和c-fos早期反应基因的表达，尽管单独使用Dex或TGF-β时无此作用。该组合协同诱导c-jun基因的表达，在24小时时达到最高水平。另一方面，c-fos基因的表达由单独的TGF-β诱导，并与Dex联合使用时呈累加性增加。用与c-jun mRNA第一外显子互补的反义寡核苷酸处理可剂量依赖性地降低Dex和TGF-β的生长抑制作用。然而，将U937细胞暴露于c-jun mRNA的正义寡聚物或c-fos mRNA的反义寡聚物中并不影响生长抑制。这些结果表明，c-jun的优先表达以及糖皮质激素反应元件介导的反式激活的刺激与用Dex和TGF-β孵育的U937细胞的生长停滞密切相关。
