A novel Ras antagonist regulates both oncogenic Ras and the tumor suppressor p53 in colon cancer cells
A novel Ras antagonist regulates both oncogenic Ras and the tumor suppressor p53 in colon cancer cells
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DOI：
10.1007/bf03402049
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发表时间：
2000-08-01
影响因子：
5.7
通讯作者：
Jansen, B
中科院分区：
文献类型：
--
作者：
Halaschek-Wiener, J;Wacheck, V;Jansen, B
背景资料：在结肠癌中，似乎与化疗耐药性和预后不良有关的K-Ras癌基因在超过50%的病例中被激活，而肿瘤抑制基因p53在约70%的病例中发生突变。转录因子p53在密码子273处频繁突变，保持野生型构型并可能执行残余功能。虽然阻断活化的K-Ras可能构成这种治疗抗性恶性肿瘤的合理治疗概念，但影响致癌Ras和肿瘤抑制因子p53的策略可能更有前途。我们评价了新型Ras拮抗剂S-反式，反式-法呢基-硫代水杨酸（FTS）对人结肠癌细胞SW 480和HT-29的作用，它们都含有p53 His 273突变，但分别表达活化的K-Ras和野生型，但过表达的H-Ras。除了细胞生长和形态学，细胞Ras蛋白水平，p53和p21（（waf 1/cip 1））表达的调节进行了分析，通过免疫印迹。流式细胞术定量测定FTS的细胞周期阻滞潜力：结果：我们证明FTS处理改变了SW 480和HT-29结肠癌细胞的形态，并通过减少Pas的总量和上调肿瘤抑制因子p53来阻断其生长。此外，FTS引起细胞周期蛋白依赖性激酶（CDK）抑制剂p21（（waf 1/cip 1））的上调，并阻断细胞周期。p53反义寡核苷酸不仅降低了p53蛋白的表达，而且相应地阻断了p21的表达（（waf 1/cip 1））。结论：FTS，一种能够调节致癌Ras和肿瘤抑制因子p53的独特化合物可以证明特别适用于结肠癌的治疗和其它治疗，抗性恶性肿瘤，其中Ras被改变，并且p53是野生型或在允许残留p53功能的位置突变。
Background: In colon cancer, K-Ras oncogenes, which appear to be linked to chemoresistance and poor prognosis, are activated in more than 50% of cases, whereas the tumor suppressor gene p53 is mutationally altered in about 70% of all cases. The transcription factor p53, which is frequently :mutated at codon 273, maintains wild-type configuration and possibly carries out residual functions. Although blocking of activated K-Ras may constitute a rational therapeutic concept for this treatment-resistant malignancy, a strategy influencing both oncogenic Ras and the tumor suppressor p53 may be even more promising.Materials and Methods: We evaluated the effects of S-trans, trans-farnesyl-thiosalicylic acid (FTS), a novel Ras antagonist on human SW480 and HT-29 colon cancer cells, which both harbor a p53 His273 mutation but express activated K-Ras and wild-type, but overexpressed, H-Ras, respectively. Besides cell growth and morphology, levels of cellular Ras proteins, regulation of p53 and p21((waf1/cip1)) expression were analyzed by immunoblotting. The cell cycle arresting potential of FTS was quantified by flow cytometry:Results: We demonstrate that]FTS treatment alters the morphology and blocks the growth of SW480 and HT-29 colon cancer cells by both reducing the total amount of Pas and up-regulating the tumor suppressor p53. Furthermore, FTS caused an upregulation of the cyclin-cyclin-dependent kinase (CDK) inhibitor p21((waf1/cip1)) and blocked the cell cycle. p53 antisense oligonucleotides not only reduced the level of p53 proteins but correspondingly also blocked the expression of p21((waf1/cip1)) in FTS-treated colon cancer cells.Conclusions: FTS, a unique compound capable of regulating both oncogenic Ras and the tumor suppressor p53 may prove particularly useful for the therapy of colon cancer and other treatment-resistant malignancies where Ras is altered and p53 is either wild-type or mutated in positions that allow residual p53 functions.