Institute of General Pathology, Catholic University School of Medicine, L. Go F. Vito, 00168 Rome, Italy.
Carcinogenesis. 2010 Oct;31(10):1813-21. doi: 10.1093/carcin/bgq157. Epub 2010 Aug 10.
Several evidences suggest that cancer cells have abnormal cholesterol biosynthetic pathways and prenylation of small guanosine triphosphatase proteins. Tomato lycopene has been suggested to have beneficial effects against certain types of cancer, including that of prostate, although the exact molecular mechanism(s) is unknown. We tested the hypothesis that lycopene may exert its antitumor effects through changes in mevalonate pathway and in Ras activation. Incubation of the Ras-activated prostatic carcinoma LNCaP cells with a 24 h lycopene treatment (2.5-10 μM) dose dependently reduced intracellular total cholesterol by decreasing 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase expression and by inactivating Ras, as evidenced by its translocation from cell membranes to cytosol. Concomitantly, lycopene reduced the Ras-dependent activation of nuclear factor-kappaB (NF-κB). Such a reduction was parallel to an inhibition of reactive oxygen species production and to a decrease in the phosphorylation ofc-jun N-terminal kinase, extracellular signal-regulated kinase 1/2 and p38. These effects were also accompanied by an arrest of cell cycle progression and by apoptosis induction, as evidenced by a decrease in cyclin D1 and phospho-AKT levels and by an increase in p21, p27 and p53 levels and in Bax:Bcl-2 ratio. The addition of mevalonate prevented the growth-inhibitory effects of lycopene as well as its increase in Ras cytoplasmatic accumulation and the subsequent changes in NF-κB. The ability of lycopene in inhibiting HMG-CoA reductase expression and cell growth and in inactivating Ras was also found in prostate PC-3, colon HCT-116 and HT-29 and lung BEN cancer cells. These findings provide a novel mechanistic insight into the growth-inhibitory effects of lycopene in cancer.
有几项证据表明，癌细胞的胆固醇生物合成途径和小 GTP 酶蛋白的prenylation 异常。番茄红素已被认为对某些类型的癌症（包括前列腺癌）有有益的影响，尽管确切的分子机制尚不清楚。我们测试了这样一个假设，即番茄红素可能通过改变甲羟戊酸途径和 Ras 激活来发挥其抗肿瘤作用。用 24 小时番茄红素处理（2.5-10 μM）孵育 Ras 激活的前列腺癌细胞 LNCaP，可降低细胞内总胆固醇，方法是降低 3-羟基-3-甲基戊二酰基辅酶 A（HMG-CoA）还原酶的表达并使 Ras 失活，如 Ras 从细胞膜转位到细胞质所证明的那样。同时，番茄红素降低了 Ras 依赖性核因子-κB（NF-κB）的激活。这种减少与活性氧（ROS）产生的抑制以及 c-jun N 末端激酶、细胞外信号调节激酶 1/2 和 p38 的磷酸化减少平行。这些作用还伴随着细胞周期进程的停滞和凋亡的诱导，如 cyclin D1 和磷酸化 AKT 水平的降低以及 p21、p27 和 p53 水平的增加以及 Bax：Bcl-2 比率的增加所证明的那样。添加甲羟戊酸可防止番茄红素的生长抑制作用及其增加 Ras 细胞质积聚以及随后 NF-κB 的变化。在前列腺 PC-3、结肠 HCT-116 和 HT-29 以及肺 BEN 癌细胞中，也发现了番茄红素抑制 HMG-CoA 还原酶表达和细胞生长以及使 Ras 失活的能力。这些发现为番茄红素抑制癌症生长的作用提供了新的机制见解。
