Huang Hai, Lee Mee-Hyun, Liu Kangdong, Dong Zigang, Ryoo Zeayoung, Kim Myoung Ok
Department of Animal Science and Biotechnology, ITRD, Kyungpook National University, Sangju 37224, Korea.
China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China.
Cancers (Basel). 2021 May 6;13(9):2232. doi: 10.3390/cancers13092232.
T-lymphokine-activated killer cell-originated protein kinase (TOPK, also known as PDZ-binding kinase or PBK) plays a crucial role in cell cycle regulation and mitotic progression. Abnormal overexpression or activation of TOPK has been observed in many cancers, including colorectal cancer, triple-negative breast cancer, and melanoma, and it is associated with increased development, dissemination, and poor clinical outcomes and prognosis in cancer. Moreover, TOPK phosphorylates p38, JNK, ERK, and AKT, which are involved in many cellular functions, and participates in the activation of multiple signaling pathways related to MAPK, PI3K/PTEN/AKT, and NOTCH1; thus, the direct or indirect interactions of TOPK make it a highly attractive yet elusive target for cancer therapy. Small molecule inhibitors targeting TOPK have shown great therapeutic potential in the treatment of cancer both in vitro and in vivo, even in combination with chemotherapy or radiotherapy. Therefore, targeting TOPK could be an important approach for cancer prevention and therapy. Thus, the purpose of the present review was to consider and analyze the role of TOPK as a drug target in cancer therapy and describe the recent findings related to its role in tumor development. Moreover, this review provides an overview of the current progress in the discovery and development of TOPK inhibitors, considering future clinical applications.
T淋巴细胞激活的杀伤细胞源蛋白激酶（TOPK，也称为PDZ结合激酶或PBK）在细胞周期调控和有丝分裂进程中发挥着关键作用。在许多癌症中，包括结直肠癌、三阴性乳腺癌和黑色素瘤，均观察到TOPK异常过表达或激活，并且它与癌症的进展、扩散增加以及不良临床结局和预后相关。此外，TOPK使参与多种细胞功能的p38、JNK、ERK和AKT磷酸化，并参与与MAPK、PI3K/PTEN/AKT和NOTCH1相关的多种信号通路的激活；因此，TOPK的直接或间接相互作用使其成为癌症治疗中一个极具吸引力但难以捉摸的靶点。靶向TOPK的小分子抑制剂在体外和体内治疗癌症方面均显示出巨大的治疗潜力，甚至与化疗或放疗联合使用时也是如此。因此，靶向TOPK可能是癌症预防和治疗的重要方法。因此，本综述的目的是考虑和分析TOPK作为癌症治疗药物靶点的作用，并描述与其在肿瘤发展中的作用相关的最新发现。此外，本综述概述了TOPK抑制剂发现和开发的当前进展，并考虑了其未来的临床应用。
