Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that leucinostatin (LCS)-A, a peptide mycotoxin, inhibited prostate cancer DU-145 cell growth through reduction of insulin-like growth factor 1 (IGF-I) expression in PrSCs. To further obtain additional bioactive compounds from LCS-A, we designed and synthesized a series of LCS-A derivatives as compounds that target PrSCs. Among the synthesized LCS-A derivatives, LCS-7 reduced IGF-I expression in PrSCs with lower toxicity to PrSCs and mice than LCS-A. As LCS-A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF-I expression in the PrSCs. As expected, LCS-A and LCS-7 directly interacted with mitochondrial ATP synthase, and like LCS-A and LCS-7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF-I by PrSCs. Furthermore, LCS-A and LCS-7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases-IGF-I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.

中文翻译：

---

线粒体ATP合酶的抑制通过前列腺基质细胞分泌的胰岛素样生长因子-1减少而抑制了前列腺癌的生长。

肿瘤组织内前列腺基质细胞（PrSCs）的调制正受到实体瘤治疗的关注。使用我们最初的体外共培养系统，我们先前曾报道亮氨酸抑素（LCS）-A，一种肽类真菌毒素，通过减少PrSC中胰岛素样生长因子1（IGF-1）的表达来抑制前列腺癌DU-145细胞的生长。为了进一步从LCS-A获得其他生物活性化合物，我们设计并合成了一系列LCS-A衍生物作为靶向PrSC的化合物。在合成的LCS-A衍生物中，LCS-7减少了PrSCs中的IGF-I表达，对PrSCs和小鼠的毒性比LCS-A低。由于已经提出LCS-A与线粒体三磷酸腺苷（ATP）合酶相互作用，因此进行了对接研究以阐明PrSC中IGF-1表达减少的机制。不出所料 LCS-A和LCS-7与线粒体ATP合酶直接相互作用，并且像LCS-A和LCS-7一样，其他线粒体ATP合酶抑制剂也降低了PrSC的IGF-1的表达。此外，LCS-A和LCS-7显着降低了小鼠异种移植肿瘤的生长。基于这些数据，我们建议PrSCs的线粒体ATP合酶-IGF-I轴对癌细胞的生长起关键作用，抑制作用可能是前列腺癌的潜在抗癌靶标。