Metastatic castration-resistant prostate cancer (CRPC) is currently incurable. Cancer growth and progression is intimately affected by its interaction with host microenvironment. Cotargeting of the stroma and prostate cancer is therefore an emerging therapeutic strategy for metastatic CRPC. Cancer-induced osteoclastogenesis is known to contribute to CRPC bone metastasis. This study is to extend pharmacologic value of our synthesized LCC03, a derivative of 5-(2',4'-difluorophenyl)-salicylanilide that has previously testified for its osteoclastogenesis activity, by exploring its additional cytotoxic properties and underlying mechanism in CRPC cells. LCC03 was chemically synthesized and examined for cell growth inhibition in a serial of CRPC cell lines. We demonstrated that LCC03 dose-dependently suppressed proliferation and retarded cell-cycle progression in CRPC cells. The classical autophagy features, including autophagosome formation and LC3-II conversion, were dramatically shown in LCC03-treated CRPC cells, and it was associated with the suppressed AKT/mTOR signaling pathways, a major negative regulator of autophagy. Moreover, an expanded morphology of the endoplasmic reticulum (ER), increased expression of the ER stress markers GRP78 and PERK, and eIF2α phosphorylation were observed. Blockage of autophagy and PERK pathways using small molecule inhibitors or shRNA knockdown reversed LCC03-induced autophagy and cell death, thus indicating that the PERK-eIF2α pathway contributed to the LCC03-induced autophagy. Furthermore, treatment of tumor-bearing mice with intraperitoneal administered LCC03 suppressed the growth of CRPC xenografts in mouse bone without systemic toxicity. The dual action of 5-(2',4'-difluorophenyl)-salicylanilide on targeting both the osteoclasts and the tumor cells strongly indicates that LCC03 is a promising anticancer candidate for preventing and treating metastatic CRPC.

中文翻译：

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一种新的水杨酰苯胺衍生物通过ER应力激活的PERK信号通路在去势抵抗性前列腺癌中诱导自噬细胞死亡。

目前无法治愈转移性去势抵抗性前列腺癌（CRPC）。癌症的生长和进展受其与宿主微环境的相互作用的密切影响。因此，基质和前列腺癌的共同靶向是转移性CRPC的新兴治疗策略。已知由癌症引起的破骨细胞形成可促进CRPC骨转移。这项研究旨在通过探索其在CRPC细胞中的其他细胞毒性特性和潜在机制，来扩展我们合成的LCC03（5-（2'，4'-二氟苯基）-水杨酰苯胺的衍生物的药理价值），该衍生物先前已证明其破骨细胞生成活性。化学合成LCC03，并检查一系列CRPC细胞系对细胞生长的抑制作用。我们证明了LCC03剂量依赖性地抑制了CRPC细胞的增殖并延缓了细胞周期进程。经典的自噬功能，包括自噬体形成和LC3-II转化，在LCC03处理的CRPC细胞中得到了显着显示，并且它与自噬的主要负调节因子AKT / mTOR信号通路受到抑制有关。此外，观察到内质网（ER）的形态扩展，ER应激标志物GRP78和PERK的表达增加，以及eIF2α磷酸化。使用小分子抑制剂或shRNA敲低阻断自噬和PERK途径逆转了LCC03诱导的自噬和细胞死亡，因此表明PERK-eIF2α途径有助于LCC03诱导的自噬。此外，腹膜内给予LCC03的荷瘤小鼠治疗可抑制CRPC异种移植物在小鼠骨骼中的生长，而无全身毒性。5-（2'，4'-二氟苯基）-水杨酰苯胺对靶向破骨细胞和肿瘤细胞的双重作用强烈表明LCC03是用于预防和治疗转移性CRPC的有前途的抗癌候选药物。