Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.
Department of Oncology, Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, China.
J Cell Physiol. 2021 Apr;236(4):2767-2781. doi: 10.1002/jcp.30134. Epub 2020 Nov 13.
Cervical cancer is the fourth most frequent cancer in women worldwide. PDZ-binding kinase (PBK) is proven to promote the malignant behaviors of various carcinomas. However, its functional roles and oncogenic mechanisms in cervical cancer are poorly understood. In this study, we reported that PBK was highly expressed in cervical cancer tissues. PBK promoted the proliferation, metastasis, and cisplatin resistance of cervical cancer cells. OTS514, a specific PBK inhibitor, could significantly suppress proliferation and metastasis of cervical cancer cells in vitro and in a xenograft model. Besides, OTS514 could enhance cisplatin-based chemosensitivity in cervical cancer cells. Mechanistically, PBK promoted the expression and stabilization of c-Myc through phosphorylating ERK1/2. OTS514 suppressed the phosphorylation of ERK1/2 and the transcriptional activity of c-Myc. Furthermore, inhibition of the ERK signal pathway by U0126 reversed the increased proliferation and metastasis induced by overexpression of PBK. Exogenous expression of c-Myc counteracted the decreased proliferation and metastasis evoked by knockdown of PBK. In conclusion, PBK promoted the malignant progression of cervical cancer through ERK/c-Myc signal pathway. PBK might be a promising molecular target for cervical cancer treatment.
宫颈癌是全世界女性中第四常见的癌症。PDZ 结合激酶 (PBK) 已被证明可促进各种癌的恶性行为。然而，其在宫颈癌中的功能作用和致癌机制仍知之甚少。在这项研究中，我们报告 PBK 在宫颈癌组织中高表达。PBK 促进了宫颈癌细胞的增殖、转移和顺铂耐药性。OTS514 是一种特异性 PBK 抑制剂，可显著抑制宫颈癌细胞在体外和异种移植模型中的增殖和转移。此外，OTS514 可增强宫颈癌细胞对顺铂为基础的化疗的敏感性。在机制上，PBK 通过磷酸化 ERK1/2 促进 c-Myc 的表达和稳定。OTS514 抑制 ERK1/2 的磷酸化和 c-Myc 的转录活性。此外，U0126 抑制 ERK 信号通路可逆转 PBK 过表达引起的增殖和转移增加。外源性表达 c-Myc 可拮抗 PBK 敲低引起的增殖和转移减少。总之，PBK 通过 ERK/c-Myc 信号通路促进了宫颈癌的恶性进展。PBK 可能是宫颈癌治疗的有前途的分子靶点。
