Ranzato Elia, Bonsignore Gregorio, Martinotti Simona
DiSIT-Dipartimento di Scienze e Innovazione Tecnologica, University of Piemonte Orientale, Viale Teresa Michel 11, 15121 Alessandria, Italy.
Cancers (Basel). 2022 Aug 26;14(17):4126. doi: 10.3390/cancers14174126.
Malignant mesothelioma is a rare cancer arising from the serosal surfaces of the body, mainly from the pleural layer. This cancer is strongly related to asbestos exposure and shows a very inauspicious prognosis, because there are scarce therapeutic options for this rare disease. Thus, there is an urgent need to develop novel therapeutic approaches to treat this form of cancer. To explore the biology of malignant pleural mesothelioma (MPM), we previously observed that MPM cell lines show high expression of the GRP78 protein, which is a chaperone protein and the master regulator of the unfolded protein response (UPR) that resides in the endoplasmic reticulum (ER). Based on our previous studies showing the importance of GRP78 in MPM, we observed that BOLD-100, a specific modulator of GRP78 and the UPR, shows cytotoxicity against MPM cells. Our studies demonstrated that BOLD-100 increases ROS production and Ca release from the ER, leading to ER stress activation and, ultimately, to cell death. Our in vitro data strongly suggest that BOLD-100 inhibits the growth of MPM cell lines, proposing the application as a single agent, or in combination with other standard-of-care drugs, to treat MPM.
恶性间皮瘤是一种起源于身体浆膜表面的罕见癌症，主要源自胸膜层。这种癌症与接触石棉密切相关，且预后非常不佳，因为针对这种罕见疾病的治疗选择很少。因此，迫切需要开发新的治疗方法来治疗这种癌症。为了探究恶性胸膜间皮瘤（MPM）的生物学特性，我们之前观察到MPM细胞系中GRP78蛋白表达很高，GRP78是一种伴侣蛋白，也是内质网（ER）中未折叠蛋白反应（UPR）的主要调节因子。基于我们之前显示GRP78在MPM中重要性的研究，我们观察到GRP78和UPR的特异性调节剂BOLD-100对MPM细胞具有细胞毒性。我们的研究表明，BOLD-100会增加活性氧（ROS）的产生以及内质网中钙的释放，导致内质网应激激活，并最终导致细胞死亡。我们的体外数据强烈表明，BOLD-100可抑制MPM细胞系的生长，建议将其作为单一药物或与其他标准治疗药物联合应用于治疗MPM。
