Erlich Shlomit, Tal-Or Pazit, Liebling Ronit, Blum Roy, Karunagaran Devarajan, Kloog Yoel, Pinkas-Kramarski Ronit
Department of Neurobiochemistry, Tel-Aviv University, Ramat-Aviv 69978, Israel.
Biochem Pharmacol. 2006 Aug 14;72(4):427-36. doi: 10.1016/j.bcp.2006.05.007. Epub 2006 May 13.
Prostate cancer is one of the most frequently diagnosed cancers in human males. Progression of these tumors is facilitated by autocrine/paracrine growth factors which activate critical signaling cascades that promote prostate cancer cell growth, survival and migration. Among these, Ras pathways have a major role. Here we examined the effect of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS), on growth and viability of androgen-dependent and androgen-independent prostate cancer cells. FTS downregulated Ras, inhibited signaling to Akt and reduced the levels of cell-cycle regulatory proteins including cyclin D1, p-RB, E2F-1 and cdc42 in LNCaP and PC3 cells. Consequently the anchorage-dependent and anchorage-independent growth of LNCaP and PC3 cells were inhibited. FTS also induced apoptotic cell death which was inhibited by the broad-spectrum caspases inhibitor, Boc-asp-FMK. Our study demonstrated that androgen-dependent and androgen-independent prostate cancer cells require active Ras for growth and survival. Ras inhibition by FTS results in growth arrest and cell death. FTS may be qualified as a potential agent for the treatment of prostate cancer.
前列腺癌是男性中最常被诊断出的癌症之一。这些肿瘤的进展由自分泌/旁分泌生长因子推动，这些因子激活关键信号级联反应，促进前列腺癌细胞的生长、存活和迁移。其中，Ras通路起主要作用。在此，我们研究了Ras抑制剂S-反式，反式-法尼基硫代水杨酸（FTS）对雄激素依赖性和雄激素非依赖性前列腺癌细胞生长和活力的影响。FTS下调Ras，抑制向Akt的信号传导，并降低LNCaP和PC3细胞中包括细胞周期蛋白D1、p-RB、E2F-1和cdc42在内的细胞周期调节蛋白水平。因此，LNCaP和PC3细胞的贴壁依赖性和非贴壁依赖性生长均受到抑制。FTS还诱导凋亡性细胞死亡，而这种死亡被广谱半胱天冬酶抑制剂Boc-asp-FMK抑制。我们的研究表明，雄激素依赖性和雄激素非依赖性前列腺癌细胞的生长和存活需要活性Ras。FTS对Ras的抑制导致生长停滞和细胞死亡。FTS可能有资格作为治疗前列腺癌的潜在药物。
