Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-0301, Japan.
Int J Cancer. 2010 Feb 15;126(4):810-8. doi: 10.1002/ijc.24915.
Targeting stroma in tumor tissues is an attractive new strategy for cancer treatment. We developed in vitro coculture system, in which the growth of human prostate cancer DU-145 cells is stimulated by prostate stromal cells (PrSC) through insulin-like growth factor I (IGF-I). Using this system, we have been searching for small molecules that inhibit tumor growth through modulation of tumor-stromal cell interactions. As a result, we have found that leucinostatins and atpenins, natural antifungal antibiotics, inhibit the growth of DU-145 cells cocultured with PrSC more strongly than that of DU-145 cells alone. In this study we examined the antitumor effects of these small molecules in vitro and in vivo. When DU-145 cells were coinoculated with PrSC subcutaneously in nude mice, leucinostatin A was found to significantly suppress the tumor growth more than atpenin B. The antitumor effect of leucinostatin A in vivo was not obtained against the tumors of DU-145 cells alone. RT-PCR experiments revealed that leucinostatin A specifically inhibited IGF-I expression in PrSC without effect on expressions of other IGF axis molecules. Leucinostatins and atpenins are known to abrogate mitochondrial functions. However, when we used mitochondrial DNA-depleted, pseudo-rho(0) cells, we found that one of leucinostain A actions certainly depended on mitochondrial function, but it actually inhibited the growth of DU-145 cells more strongly in coculture with pseudo-rho(0) PrSC and reduced IGF-I expression in pseudo-rho(0) PrSC. Taken together, our results suggested that leucinostatin A inhibited prostate cancer cell growth through reduction of IGF-I expression in PrSC.
靶向肿瘤组织中的基质是癌症治疗的一种新的有吸引力的策略。我们开发了体外共培养系统，其中人前列腺癌细胞 DU-145 的生长通过胰岛素样生长因子 I（IGF-I）被前列腺基质细胞（PrSC）刺激。使用该系统，我们一直在寻找通过调节肿瘤-基质细胞相互作用来抑制肿瘤生长的小分子。结果，我们发现亮抑酶肽和阿普亭，天然抗真菌抗生素，比单独培养的 DU-145 细胞更强烈地抑制与 PrSC 共培养的 DU-145 细胞的生长。在这项研究中，我们在体外和体内检查了这些小分子的抗肿瘤作用。当 DU-145 细胞与 PrSC 一起皮下接种到裸鼠中时，发现亮抑酶肽 A 显著抑制肿瘤生长，比阿普亭 B 更有效。亮抑酶肽 A 在体内对单独的 DU-145 细胞肿瘤没有抗肿瘤作用。RT-PCR 实验表明，亮抑酶肽 A 特异性抑制 PrSC 中的 IGF-I 表达，而对其他 IGF 轴分子的表达没有影响。亮抑酶肽和阿普亭已知会破坏线粒体功能。然而，当我们使用线粒体 DNA 耗尽的 pseudo-rho(0) 细胞时，我们发现亮抑酶肽 A 的一种作用肯定依赖于线粒体功能，但它实际上在与 pseudo-rho(0) PrSC 的共培养中更强烈地抑制 DU-145 细胞的生长，并降低 pseudo-rho(0) PrSC 中的 IGF-I 表达。总之，我们的结果表明亮抑酶肽 A 通过减少 PrSC 中的 IGF-I 表达抑制前列腺癌细胞的生长。
