Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.
卵巢癌是致死率最高的妇科恶性肿瘤，其在分子、细胞及组织层面的肿瘤异质性导致肿瘤对标准疗法产生耐药性，构成重大临床挑战。本研究验证以下假设：卵巢癌中观察到的基础内质网应激水平升高可作为可利用的治疗靶点，并可能克服肿瘤异异性。我们近期研究发现，小分子化合物ERX-41可通过靶向LIPA诱导癌细胞发生内质网应激，但LIPA在卵巢癌中的作用及ERX-41的治疗潜力尚不明确。通过TNMplot网络工具、TCGA数据库分析及肿瘤组织芯片免疫组化实验，发现LIPA在卵巢癌组织中较正常组织显著高表达。ERX-41处理能显著降低卵巢癌细胞活力、抑制克隆形成能力并促进细胞凋亡。机制研究表明，ERX-41处理可稳定诱导CHOP、elF2α、PERK和ATF4等内质网应激标志物表达。在异种移植模型和患者来源移植瘤模型中，ERX-41治疗显著抑制肿瘤生长。综上，本研究证实ERX-41是通过靶向LIPA诱导内质网应激的新型治疗剂，其独特作用机制为治疗卵巢癌异质性提供了新策略。
肿瘤(癌症)患者之家