Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Department of Pathology and Molecular Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Mol Cancer Ther. 2014 Dec;13(12):2817-26. doi: 10.1158/1535-7163.MCT-14-0522. Epub 2014 Sep 24.
Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 is most potent. The purposes of this study were to further investigate the effects of targeting PCNA chromatin association on DNA damage and cytotoxicity and to evaluate the therapeutic potential of PCNA-I1 against tumors in mice. Given the important roles of tumor suppressor p53 in regulating sensitivity of tumor cells to chemotherapeutics, we performed studies in two human prostate cancer cell lines differing in p53 expression: LNCaP cells (wild-type p53) and PC-3 cells (p53-null). PCNA-I1 induced DNA damage and apoptosis in both LNCaP and PC-3 cells and enhanced DNA damage and apoptosis triggered by cisplatin. PCNA-I1 also induced autophagy in PC-3 cells. A short-term pretreatment with PCNA-I1 reduced colony formation by 50% in both cell lines. These data suggest that, unlike many other cytotoxic drugs, the effects of PCNA-I1 on tumor cells do not depend on expression of p53. Intravenous administrations of PCNA-I1 significantly retarded growth of LNCaP tumors of in nude mice without causing detectable effects on mouse body weight and hematology profiles. These data provide proof of concept that targeting PCNA chromatin association could be a novel and effective therapeutic approach for treatment of cancer.
增殖细胞核抗原（PCNA）在 DNA 复制和修复中发挥着重要作用。肿瘤细胞表达高水平的 PCNA，使其成为癌症治疗的潜在理想靶点。先前，我们鉴定了九种称为 PCNA 抑制剂（PCNA-Is）的化合物，它们直接与 PCNA 结合，稳定 PCNA 三聚体结构，减少染色质相关的 PCNA，并选择性地抑制肿瘤细胞生长。在这些化合物中，PCNA-I1 的活性最强。本研究的目的是进一步研究靶向 PCNA 染色质结合对 DNA 损伤和细胞毒性的影响，并评估 PCNA-I1 对小鼠肿瘤的治疗潜力。鉴于肿瘤抑制因子 p53 在调节肿瘤细胞对化疗药物敏感性方面的重要作用，我们在两种人前列腺癌细胞系中进行了研究，这两种细胞系在 p53 表达上存在差异：LNCaP 细胞（野生型 p53）和 PC-3 细胞（p53 缺失）。PCNA-I1 诱导 LNCaP 和 PC-3 细胞中的 DNA 损伤和细胞凋亡，并增强顺铂引发的 DNA 损伤和细胞凋亡。PCNA-I1 还诱导 PC-3 细胞发生自噬。短期预处理 PCNA-I1 可使两种细胞系的集落形成减少 50%。这些数据表明，与许多其他细胞毒性药物不同，PCNA-I1 对肿瘤细胞的作用不依赖于 p53 的表达。静脉给予 PCNA-I1 可显著延缓裸鼠 LNCaP 肿瘤的生长，而对小鼠体重和血液学特征没有可检测的影响。这些数据提供了概念验证，即靶向 PCNA 染色质结合可能是治疗癌症的一种新的有效治疗方法。
