Egozi Y, Weisz B, Gana-Weisz M, Ben-Baruch G, Kloog Y
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
Int J Cancer. 1999 Mar 15;80(6):911-8. doi: 10.1002/(sici)1097-0215(19990315)80:6<911::aid-ijc18>3.0.co;2-4.
A lipophilic farnesyl moiety attached to the carboxyl terminal cysteine of ras proteins structurally supports their membrane anchorage, required for ras-dependent growth-factor signaling and for transforming activity of ras oncoproteins. It has been shown that inhibition of ras farnesylation can block tumor growth in nude mice but that some ras-dependent tumors escape such blockage as a result of prenylation of ras. S-trans-transfarnesylthiosalicylic acid (FTS) is a potent ras-dislodging antagonist that does not affect ras prenylation but rather acts on the mature, membrane-bound ras and facilitates its degradation. Here we demonstrate that FTS induces reappearance of stress fibers in H-ras-transformed rat-1 cells (EJ cells) in vitro, inhibits their anchorage-independent growth in vitro, and blocks EJ-tumor growth in nude mice. The anchorage-independent growth of cells expressing ErbB2 (B104), but not that of v-raf-transformed cells, is also inhibited by FTS, suggesting specificity towards activated ras. FTS treatment (5 mg/kg i.p. daily) caused inhibition (75-80%) of tumor growth in nude mice implanted with EJ, but not in mice implanted with v-raf-transformed cells, with no evidence of systemic toxicity. Moreover, FTS treatment increased the survival rate of EJ-tumor-bearing mice from 48 to 68 days. Here we demonstrate anti-tumor potency in a synthetic, non-toxic, ras-dislodging antagonist acting independently of farnesyltransferases.
与ras蛋白羧基末端半胱氨酸相连的亲脂性法尼基部分在结构上支持其膜锚定，这是ras依赖的生长因子信号传导和ras癌蛋白转化活性所必需的。研究表明，抑制ras法尼基化可阻断裸鼠肿瘤生长，但一些ras依赖的肿瘤会因ras的异戊二烯化而逃避这种阻断。S-反式-反式法尼基硫代水杨酸（FTS）是一种有效的ras解离拮抗剂，它不影响ras的异戊二烯化，而是作用于成熟的、膜结合的ras并促进其降解。在此我们证明，FTS在体外可诱导H-ras转化的大鼠-1细胞（EJ细胞）中应力纤维重新出现，抑制其体外非锚定依赖性生长，并阻断裸鼠体内EJ肿瘤的生长。FTS也抑制表达ErbB2的细胞（B104）的非锚定依赖性生长，但不抑制v-raf转化细胞的非锚定依赖性生长，这表明其对活化的ras具有特异性。FTS处理（每天腹腔注射5mg/kg）可抑制接种EJ的裸鼠肿瘤生长（75 - 80%），但对接种v-raf转化细胞的小鼠无效，且无全身毒性证据。此外，FTS处理将荷EJ肿瘤小鼠的存活率从48天提高到68天。在此我们证明了一种合成的、无毒的、独立于法尼基转移酶起作用的ras解离拮抗剂具有抗肿瘤效力。
