Targeting z-Crystallin by aspirin restores the sensitivity to cisplatin in resistant A2780 ovarian cancer cells

Ovarian cancer is the deadliest gynaecologic malignancies worldwide. Platinum based chemotherapy is the mainstay treatment for ovarian cancer; however, frequent recurrence and chemoresistance onset in patients with advanced diseases remain a therapeutic challenge. Although mechanisms underlying the development of chemoresistance are still ambiguous, the B-cell lymphoma-2 (Bcl-2) family is closely associated with chemoresistance in ovarian cancer. We previously disclosed that Zeta-Crystallin (CryZ) is a post-transcriptional regulator of Bcl-2 gene expression, by binding to Bcl-2 mRNA and increasing its half-life. Here, we investigated the role of CryZ as a novel therapeutic target in A2780 ovarian carcinoma cells by modulating the protein activity with acetylsalicylic acid (ASA) to restore chemosensitivity. Molecular docking and fragment-mapping based approach revealed potential interaction of ASA within CryZ protein. Inhibition of CryZ binding activity to Bcl-2 and Bcl-xl mRNA targets by ASA was demonstrated in A375 cells. Cytotoxicity assays were conducted in A2780S and A2780R ovarian cancer cells to evaluate if CryZ binding activity inhibition and CryZ silencing were able to reverse cisplatin resistance. ASA-treatment determined a downregulation of Bcl-2 and Bcl-xl mRNA levels in A2780S and A2780R cells. ASA-treatment or CryZ silencing were able to increase and restore the chemosensitivity in both sensitive and resistant A2780 ovarian cancer cells, respectively. ​In this research article we demonstrated that the pharmacological or genetic inhibition of CryZ restores the sensitivity to cisplatin in a model of sensitive or resistant ovarian cancer cells. These findings suggest a new gene-targeted chemotherapeutic approach to restore the cytotoxicity in drug-resistant ovarian cancers and increase the sensitivity in non-resistant cells. We investigated the role of CryZ as a novel therapeutic target in A2780 ovarian carcinoma cells by modulating the protein activity with acetylsalicylic acid (ASA) to restore chemosensitivity. Molecular docking and fragment-mapping based approach revealed potential interaction of ASA within CryZ protein

卵巢癌是全球致死率最高的妇科恶性肿瘤。铂类化疗是卵巢癌的一线治疗方案，但晚期患者常出现复发与化疗耐药，仍是临床治疗的棘手难题。尽管化疗耐药的具体发生机制仍不明晰，但B细胞淋巴瘤-2（B-cell lymphoma-2, Bcl-2）家族与卵巢癌化疗耐药密切相关。本课题组此前已证实，ζ-晶状体蛋白（Zeta-Crystallin, CryZ）可通过结合Bcl-2 mRNA并延长其半衰期，作为Bcl-2基因表达的转录后调控因子。本研究以A2780卵巢癌细胞为模型，通过乙酰水杨酸（acetylsalicylic acid, ASA）调控CryZ蛋白活性以恢复化疗敏感性，探究CryZ作为新型治疗靶点的潜力。基于分子对接与片段映射的分析方法，揭示了ASA与CryZ蛋白存在潜在结合相互作用。在A375细胞中证实，ASA可抑制CryZ与Bcl-2及B细胞淋巴瘤-xl（Bcl-xl）mRNA靶标的结合活性。本研究在A2780顺铂敏感株（A2780S）与耐药株（A2780R）卵巢癌细胞中开展细胞毒性实验，以验证抑制CryZ结合活性或敲低CryZ表达能否逆转顺铂耐药。ASA处理可降低A2780S与A2780R细胞中Bcl-2及Bcl-xl的mRNA水平。ASA处理或CryZ敲低可分别提升顺铂敏感株、恢复耐药株卵巢癌细胞的化疗敏感性。本研究证实，通过药理学或遗传学手段抑制CryZ，可在顺铂敏感或耐药的卵巢癌细胞模型中恢复其对顺铂的敏感性。上述研究结果提示，靶向CryZ的基因治疗策略可恢复耐药卵巢癌的细胞毒性，并提升非耐药卵巢癌细胞的化疗敏感性。本研究以A2780卵巢癌细胞为模型，通过乙酰水杨酸（acetylsalicylic acid, ASA）调控CryZ蛋白活性以恢复化疗敏感性，探究CryZ作为新型治疗靶点的潜力。