TOPK/PBK promotes cell migration via modulation of the PI3K/PTEN/AKT pathway and is associated with poor prognosis in lung cancer

Abstract

We integrated four gene expression profile data sets, namely two different pair-matched stage I lung adenocarcinoma data sets, secondary metastatic tumors vs benign tumors and lung tumor metastasizes to the brain, and we identified one kinase, T-LAK Cell-Originated Protein Kinase (TOPK), as a putative gene that promotes metastasis. To delineate the role of TOPK in lung cancer, we showed that overexpression of TOPK, but not a catalytically inactive form of TOPK, can enhance the migration and invasion of lung fibroblasts or cells with low TOPK expression. In addition, TOPK-induced cell migration was shown to be a PI3K/AKT-dependent event. TOPK concurrently promoted AKT phosphorylation at Ser 473 and decreased the phosphatase and tensin homolog (PTEN) levels, whereas TOPK knockdown had the reverse effects. LY294002, a PI3K inhibitor, did not inhibit the TOPK-induced decrease in PTEN, and coexpression of PTEN significantly reduced TOPK-induced AKT phosphorylation in a dose-dependent manner; these results indicate that the TOPK-mediated PTEN decrease has an upstream role in regulating PI3K/AKT-stimulated migration. Using immunohistochemical analysis of lung cancer tissue samples, we showed that a high TOPK expression level correlates strongly with reduced overall and disease-free survivals. Moreover, an inverse correlation between TOPK and PTEN expression was present and is consistent with the biochemical findings. Finally, a combination of high TOPK and low PTEN expression was inversely correlated with overall and disease-free survivals, independent of other pathologic staging factors. Our results suggest that TOPK is a potential therapeutic target in lung cancer that promotes cell migration by modulating a PI3K/PTEN/AKT-dependent signaling pathway; they also suggest that high TOPK expression, either alone or in combination with a low level of PTEN, may serve as a prognostic marker for lung cancer.

Overexpression of PBK/TOPK Contributes to Tumor Development and Poor Outcome of Esophageal Squamous Cell Carcinoma

“…PBK/TOPK prevents cancer cell death by impairing processes in the DNA damage-induced apoptosis pathway (13)(14)(15), such as tumor suppressor p53 and p38-mitogen-activated protein kinase (p38-MAPK) activities. PBK/TOPK promotes cell migration by modulating phosphoinositide 3-kinase/phosphatase and tensin homolog/ AKT (PI3K/PTEN/AKT)-dependent signaling (8). However, to date, there has been no report on the clinical and prognostic significance of PBK/TOPK in patients with ESCC and its molecular function contributing to gastric carcinogenesis.…”

“…The PBK/TOPK gene is up-regulated in various types of cancer and tumors such as bladder cancer, brain tumor, breast cancer, liver cancer, lung cancer and sarcoma (7)(8)(9)(23)(24)(25)(26). PBK/TOPK was initially identified as a mitotic protein kinase (27), assisting the recruitment of cylcin-dependent kinase 1 (CDK1)/cyclin B to mitotic spindles, where PBK/TOPK plays a role in the formation of the spindle midzone and cytokinesis (10).…”

“…highly expressed in various types of human cancer such as breast and lung cancer (7)(8)(9). Physiologically, PBK/TOPK plays a positive regulatory role in proper chromosomal separation and cytokinesis through phosphorylation of various targets (10,11).…”

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

“…It has been reported that loss of function or downregulation of PTEN resulted in tumor metastasis, and more aggressive growth behaviors of tumor, and/or poor prognostic phenotypes. 42,[49][50][51][52][53][54][55][56][57] In addition, miR-19 upregulation was observed in various cancers including lung cancer, and correlated with tumor metastasis and/or poor prognosis of cancer patients. [11][12][13][14][15]18 Given that miRNAs primarily function through inhibiting the translation of their mRNA targets, we propose that miR-19 might be a negative regulator for PTEN, which has been reported by other researchers.…”

“…Increasing evidence supports that inactivation or downregulation of the tumor suppressor PTEN can trigger EMT of cancer cells, [60][61][62][63] which then promoted the invasion and metastasis of various cancers including lung cancer. 42,[49][50][51][52][53][54][55][56][57] It has been reported that PTEN negatively regulated the PI3K/ Akt pathway through the dephosphorylation of PI(3,4,5)P3, and ultimately participated in the regulation of cell cycle, proliferation, apoptosis, adhesion, and EMT during cancer progress. 63 In the present study, we found that PTEN silence through RNA interference mimicked miR-19-induced EMT, and promoted the migration and invasion of tumor cells, which were similar as the results caused by miR-19 overexpression.…”