Liu L, Hudgins W R, Miller A C, Chen L C, Samid D
Clinical Pharmacology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Cytokine. 1995 Jul;7(5):449-56. doi: 10.1006/cyto.1995.0061.
The aromatic fatty acids phenylacetate (PA) and phenylbutyrate (PB) induce tumour cell differentiation in experimental models and both are currently in clinical trials. The purpose of this study was to determine the effect of these antitumour agents on the expression of transforming growth factor-alpha (TGF-alpha) in neoplastic cells. Treatment of human melanoma 1011 cultures with either PA or PB caused over 40-fold increase in TGF-alpha biosynthesis and secretion into the media. Whereas elevation in TGF-alpha mRNA steady-state levels became evident within 6-12 h and reached peak quantities the following day, the amounts of its coded protein increased gradually over a period of 5 days of treatment. Further molecular analysis revealed that regulation of TGF-alpha expression occurred at the transcriptional level. In contrast to TGF-alpha, expression of its receptor remained below detectable levels, indicating that an autocrine loop involving this growth factor is unlikely. Interestingly, the increase in TGF-alpha production paralleled drug-induced cytostasis and differentiation defined by morphological changes and increased melanogenesis. Like PA and PB, other differentiation inducers such as all-trans-retinoic acid, dimethyl sulfoxide, and 5-aza-2'-deoxycytidine, all induced TGF-alpha expression in the melanoma cells. The close association between enhanced TGF-alpha production and melanoma cell differentiation suggests that this growth factor, often linked to mitogenesis, may play a novel role in tumour differentiation by PA and PB.
芳香族脂肪酸苯乙酸（PA）和苯丁酸（PB）在实验模型中可诱导肿瘤细胞分化，目前二者均处于临床试验阶段。本研究的目的是确定这些抗肿瘤药物对肿瘤细胞中转化生长因子-α（TGF-α）表达的影响。用PA或PB处理人黑色素瘤1011培养物，可使TGF-α的生物合成及分泌到培养基中的量增加40倍以上。虽然TGF-α mRNA稳态水平在6至12小时内明显升高，并在第二天达到峰值，但在处理的5天时间里，其编码蛋白的量逐渐增加。进一步的分子分析表明，TGF-α表达的调控发生在转录水平。与TGF-α相反，其受体的表达仍低于可检测水平，这表明涉及该生长因子的自分泌环不太可能存在。有趣的是，TGF-α产生的增加与药物诱导的细胞停滞以及由形态变化和黑色素生成增加所定义的分化平行。与PA和PB一样，其他分化诱导剂，如全反式维甲酸、二甲基亚砜和5-氮杂-2'-脱氧胞苷，均可诱导黑色素瘤细胞中TGF-α的表达。TGF-α产生增加与黑色素瘤细胞分化之间的密切关联表明，这种通常与有丝分裂相关的生长因子可能在PA和PB诱导的肿瘤分化中发挥新的作用。
