Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses.
Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses.
复制标题
DOI：
10.1158/1078-0432.ccr-13-2658
复制
发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Bazzaro M
中科院分区：
文献类型：
--
作者：
Coughlin K;Anchoori R;Iizuka Y;Meints J;MacNeill L;Vogel RI;Orlowski RZ;Lee MK;Roden RB;Bazzaro M
卵巢癌是最致命的妇科恶性肿瘤。致癌进展伴随着泛素依赖性蛋白质降解机制的上调，作为一种机制，以补偿升高的内源性蛋白毒性应激。最近的研究支持这样一种观点，即去泛素化酶（DUB）是蛋白水解降解的重要因素，其异常活性与癌症进展和化疗耐药性有关。因此，DUB是卵巢癌的有吸引力的治疗靶点。在卵巢癌细胞系和原代细胞中测定RA-9抑制剂对蛋白酶体相关DUB的效力和选择性。RA-9的抗癌活性及其作用机制在多种癌细胞系中在体外和在携带人卵巢癌的腹膜内ES-2异种移植模型的免疫缺陷小鼠中在体内进行了评价。在这里，我们报告RA-9作为蛋白酶体相关DUBs的小分子抑制剂的特性。在卵巢癌细胞系和来源于供体的原代培养物中，用RA-9治疗选择性地诱导细胞凋亡的发生。RA-9暴露后细胞活力的丧失与未折叠蛋白反应（UPR）相关，作为补偿不可持续的蛋白毒性应激水平的机制。用RA-9的体内治疗延缓肿瘤生长，增加总存活率，并且被宿主良好耐受。我们的临床前研究支持进一步评估RA-9作为卵巢癌治疗剂。
Ovarian cancer is the deadliest of the gynecological malignancies. Carcinogenic progression is accompanied by up-regulation of ubiquitin-dependent protein degradation machinery as a mechanism to compensate with elevated endogenous proteotoxic stress. Recent studies support the notion that deubiquitinating enzymes (DUBs) are essential factors in proteolytic degradation and that their aberrant activity is linked to cancer progression and chemoresistance. Thus, DUBs are an attractive therapeutic target for ovarian cancer. The potency and selectivity of RA-9 inhibitor for proteasome-associated DUBs was determined in ovarian cancer cell lines and primary cells. The anticancer activity of RA-9 and its mechanism of action was evaluated in multiple cancer cell lines in vitro and in vivo in immunodeficient mice bearing an intra-peritoneal ES-2 xenograft model of human ovarian cancer. Here we report the characterization of RA-9 as a small-molecule inhibitor of proteasome-associated DUBs. Treatment with RA-9 selectively induces onset of apoptosis, in ovarian cancer cell lines and primary cultures derived from donors. Loss of cell viability following RA-9 exposure is associated with an Unfolded Protein Response (UPR) as mechanism to compensate for unsustainable levels of proteotoxic stress. In vivo treatment with RA-9 retards tumor growth, increases overall survival and was well tolerated by the host. Our preclinical studies support further evaluation of RA-9 as an ovarian cancer therapeutic.