Abstract
Nasopharyngeal carcinoma (NPC) is well known as one of the most common malignancies in southern China and Southeast Asia. However, the mechanisms underlying NPC progression remain poorly understood. Herein, through overlapping the differentially expressed genes from 3 microarray data sets with the human kinome, we identified PBK, a serine-threonine kinase, is highly upregulated and has not been intensively investigated in NPC. PBK was required for malignant phenotypes of NPC, as PBK depletion by RNAi and inhibition by specific inhibitor HI-TOPK-032 obviously reduced cell proliferation and xenograft tumor growth in mice. Moreover, we determined that targeting PBK could accelerate apoptosis by inducing ROS that activates JNK/p38 signaling pathway. In NPC patients, elevated PBK expression in primary tumor positively correlated to clinical severity such as advanced T stage, high death risk and disease progression, and it could serve as an unfavorable independent indicator of overall survival and disease-free survival. Altogether, our results indicate that PBK is a novel significant regulator of NPC progression and a potential therapeutic target for NPC patients.
Highlights
Nasopharyngeal carcinoma (NPC) has a high incidence rate in southern China and Southeast Asia [1,2,3]
We confirmed that PBK was a novel oncogene and a promising theranostic target for NPC
Our functional studies showed that knocking down of PBK expression suppresses cancer cell proliferation and colony formation in NPC cells, as well as HI-TOPK-032 treatment could induce a massive increase in reactive oxygen species (ROS) and activate P38/Jun N-terminal kinase (JNK) pathways to promote apoptosis
Summary
Nasopharyngeal carcinoma (NPC) has a high incidence rate in southern China and Southeast Asia [1,2,3]. Many improvements in technology and equipment of radiotherapy have been achieved, the outcome of patients with locoregionally advanced NPC is still unsatisfactory. The molecular mechanisms regulating NPC recurrence and metastasis are not fully understood. It is well known that the deregulated expression or activity of many kinases play a pivotal role in tumor biology processes including uncontrolled proliferation, metastasis and angiogenesis. PBK/TOPK, a serine-threonine kinase, is highly expressed in various cancers such as lymphoma, leukemia, melanoma, colorectal, breast cancer, lung and glioma [1419]. PBK has been recognized as a metastasis-promoting kinase that it promotes cell migration by modulating the PI3K/PTEN/AKT pathway in lung cancer [27] and is highly expressed in circulating tumor cells, enabling metastasis of prostate cancer [28]. Through the normal tissues data published recently [31] and literature mining [17], we put our intention on PBK/TOPK because it is hard to detect in vital organs except for testis and might be a promising molecular target
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