Deguelin inhibits epithelial‐to‐mesenchymal transition and metastasis of human non‐small cell lung cancer cells by regulating NIMA‐related kinase 2

Abstract

BackgroundNon‐small cell lung cancer is a lethal malignancy with a high mortality rate. Deguelin displays an anti‐tumor effect and inhibits metastasis in various cancers. The aberrant expression of NIMA‐related kinase 2 (NEK2) indicates poor prognosis and induces epithelial‐to‐mesenchymal transition (EMT) and metastasis processes. However, the underlying mechanism between deguelin and NEK2 has remained elusive.Methods NSCLC cell lines were treated with deguelin. Wound‐healing and invasion assays were applied to study the inhibitory effect of deguelin on NSCLC cells. EMT markers, E‐cadherin and Vimentin, were also detected by Western blot. NEK2 protein and messenger RNA expression levels were evaluated when NSCLC cells were treated with different concentrations of deguelin. The effect of NEK2 on NSCLC cell metastasis was evaluated through NEK2 knockdown. To investigate whether deguelin induced EMT by regulating NEK2, we overexpressed NEK2 in both NCI‐H520 and SK‐MES‐1 cell lines, and then used real time‐PCR to study the E‐cadherin and Vimentin messenger RNA expression in both NSCLC cells.ResultsDeguelin inhibited migration and invasion processes in NSCLC cell lines and decreased NEK2 expression in a concentration‐dependent manner. Furthermore, NEK2 knockdown inhibited NSCLC cell migration and invasion. Finally, overexpressing NEK2 in NCI‐H520 and SK‐MES‐1 cells could restore the inhibition of metastasis induced by deguelin.ConclusionsDeguelin could inhibit EMT and metastasis, while overexpression of NEK2 promotes these processes. Deguelin could decrease NEK2 expression, while NEK2 overexpression could restore deguelin‐induced inhibition of metastasis.

Rotenone restrains colon cancer cell viability, motility and epithelial‑mesenchymal transition and tumorigenesis in nude mice via the PI3K/AKT pathway

“…Rotenone has been reported to target NF-κb to induce EMT reversion and apoptosis in pancreatic cancer (16). In addition, rotenone can prevent the metastasis and EMT of human non-small cell lung cancer cells by modulating NIMA-related kinase 2 (18). However, the effects and underlying mechanisms of rotenone on cc metastasis and EMT require further study.…”

NIMA-Related Kinase 2 Overexpression is Associated with Poor Survival in Cancer Patients: A Systematic Review and Meta-Analysis

“…NEK2 has also been shown to be involved in abnormal cell differentiation, tumor proliferation, drug resistance, and poor prognosis in several kinds of tumors. [37][38][39] A lot of effort has been made to understand the functional role of NEK2 in cancer. Zhang et al found that NEK2 significantly enhanced the invasive ability of HCC cells, and epithelial-mesenchymal transition played a pivotal role in the NEK2-mediated promotion of HCC cell invasion.…”

Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential

“…Briefly, deguelin impedes carcinogenesis by 1) inducing cell apoptosis, 2) inhibiting tumor cell propagation, and 3) preventing malignant transformation of tumors. 16,17 Crucial oncogenic pathways likely targeted by deguelin are the phosphoinositide 3-kinase (PI3K)/Akt pathway, [18][19][20][21][22][23][24][25][26] the Wnt signaling pathway, 27,28 the epidermal growth factor receptor (EGFR) and c-Met signaling pathway, 29 the epithelial-to-mesenchymal transition (EMT) pathway, 30 the hedgehog signaling pathway, 31,32 and angiogenesis-related pathways. 33 In addition, deguelin has been identified as an Aurora B kinase inhibitor that exhibits a potent antitumor effect in human esophageal squamous cell carcinoma.…”

“…51 Since 2008, it has been widely accepted that EMTs can occur in 3 distinct biological backdrops, which lead to distinct functional consequences. 52 Deguelin has been demonstrated to act via the inhibition of EMT pathways in non-small cell lung cancer (NSCLC) cells 30 and to inhibit the metastasis of pancreatic tumors via increased expression of E-cadherin, a tight junction protein that prevents tumor dissemination (metastasis). 53 Liu et al 54 found that low-dose deguelin significantly inhibited the invasion and migration of oral cancer cells while being associated with minimal cytotoxicity and systemic toxicity.…”