Maxwell S A
Department of Thoracic and Cardiovascular Surgery, University of Texas M.D. Anderson Cancer Center, Houston.
Anticancer Res. 1994 Jul-Aug;14(4A):1535-40.
The growth of non-small cell lung carcinoma (NSCLC) cells was inhibited by retinoic acid after 16 h of treatment. However, the growth of all cell lines except one became refractory to retinoic acid after 48 h of exposure. The expression of the hyperphosphorylated retinoblastoma protein species (RB p110) was observed to be increased fivefold to tenfold in NSCLC cells within 16 h of exposure to retinoic acid. In the H460a and H226b cell lines, p110 showed some conversion to the underphosphorylated p105 form after 24 h of retinoic acid treatment. After 48 h, p105 became the predominant form, along with a 60K M(r) species. After 72 h, expression of all RB protein species became almost undetectable in H460a and H226b cells, concomitant with increases in cell growth rates. A different pattern of RB expression was observed in the H322j and H358 cell lines. In these cells, both p110 and p105 were induced within 8 h of retinoic acid treatment. Furthermore, the elevated levels and the phosphorylation state of RB in retinoic acid-treated H322j and H358 cells remained essentially unchanged for up to 72 h and only low amounts of the 60K M(r) species were detected. I believe that a post-translational mechanism is responsible for the retinoic acid-mediated induction of RB, since levels of RB mRNA remained relatively unchanged during the time course of retinoic acid exposure. I conclude that retinoic acid inhibited the growth of NSCLC cells by inducing high levels of RB and that increases in RB levels occurred as a result of either an increase in stability of the protein or by downregulation of an RB-specific protease. The inhibition of growth by retinoic acid must involve other molecular events, since the H596b cell line, which lacks RB protein, exhibited growth properties in the presence of retinoic acid similar to those of cells in which RB expression was induced.
治疗16小时后，维甲酸抑制了非小细胞肺癌（NSCLC）细胞的生长。然而，除一种细胞系外，所有细胞系在暴露48小时后对维甲酸产生了耐药性。在暴露于维甲酸的16小时内，观察到非小细胞肺癌细胞中高磷酸化视网膜母细胞瘤蛋白（RB p110）的表达增加了五到十倍。在H460a和H226b细胞系中，维甲酸处理24小时后，p110显示出向低磷酸化p105形式的一些转化。48小时后，p105成为主要形式，同时出现一种60K M(r)蛋白。72小时后，H460a和H226b细胞中所有RB蛋白的表达几乎检测不到，同时细胞生长速率增加。在H322j和H358细胞系中观察到不同的RB表达模式。在这些细胞中，维甲酸处理8小时内p110和p105均被诱导。此外，维甲酸处理的H322j和H358细胞中RB的升高水平和磷酸化状态在长达72小时内基本保持不变，仅检测到少量的60K M(r)蛋白。我认为翻译后机制负责维甲酸介导的RB诱导，因为在维甲酸暴露的时间过程中，RB mRNA水平相对保持不变。我得出结论，维甲酸通过诱导高水平的RB抑制非小细胞肺癌细胞的生长，并且RB水平的增加是由于蛋白质稳定性增加或RB特异性蛋白酶下调所致。维甲酸对生长的抑制必定涉及其他分子事件，因为缺乏RB蛋白的H596b细胞系在维甲酸存在下表现出的生长特性与诱导RB表达的细胞相似。
