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

Zhao, Dejian; Han, Wenzheng; Liu, Xia; Cui, Dawei; Chen, Yu

doi:10.1111/1759-7714.12444

Cited by 19 publications

(10 citation statements)

References 30 publications

(43 reference statements)

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“…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.…”

Section: Rotenone Restrains Colon Cancer Cell Viability Motility Andmentioning

confidence: 99%

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

Xiao

Liu

Dai³

et al. 2020

Int J Mol Med

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Rotenone, a natural hydrophobic pesticide, has been reported to display anticancer activity in a variety of cancer cells. However, the mechanism of rotenone on colon cancer (cc) cell migration, invasion and metastasis is still unknown. In the present study, the cytotoxicity of rotenone on cc cells were detected by the cell counting Kit-8 assay and confirmed by clone formation assay. The effects of rotenone on cc cell invasion and migration activity were determined in vitro by Transwell invasion and wound healing assays, respectively. In addition, to reveal whether rotenone affected the epithelial-mesenchymal-transition (EMT) process, reverse transcription-quantitative PcR, western blotting and immunofluorescence assays were used to detect the expression of EMT markers. The expression levels of the key markers of the PI3K/AKT pathway after rotenone treatment alone or in combination with a PI3K/AKT signaling activator in cc were also detected by western blotting. Finally, the in vivo antitumor effects of rotenone were evaluated in a subcutaneous xenotransplant tumor model treated with an intraperitoneal injection of rotenone. The results of the present study demonstrated that rotenone treatment induced cc cell cytotoxicity and greater effects were observed with increasing concentrations and inhibited cell proliferation compared with untreated cells. In vitro cell function assays revealed that rotenone inhibited cc cell migration, invasion and EMT compared with untreated cells. Mechanically, the phosphorylation levels of AKT and mTOR were downregulated in rotenone-treated cc cells compared with untreated cells. Additionally, AKT and mTOR phosphorylation levels were increased by the PI3K/AKT signaling activator insulin-like growth factor 1 (IGF-1), which was reversed by rotenone treatment. The cell function assays confirmed that the IGF-1-activated cell proliferation, migration and invasion were decreased by rotenone treatment. These results indicated that rotenone affected cc cell proliferation and metastatic capabilities by inhibiting the PI3K/AKT/mTOR signaling pathway. In addition, rotenone inhibited tumor growth and metastatic capability of cc, which was confirmed in a xenograft mouse model. In conclusion, the present study revealed that rotenone inhibited cc cell viability, motility, EMT and metastasis in vitro and in vivo by inhibiting the PI3K/AKT/mTOR signaling pathway.

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Section: Rotenone Restrains Colon Cancer Cell Viability Motility Andmentioning

confidence: 99%

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

Xiao

Liu

Dai³

et al. 2020

Int J Mol Med

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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NIMA-related kinase 2 (NEK2) has been reported to be overexpressed in various types of cancer and correlated with poor prognosis. The role(s) of NEK2 in cancer, however, is still uncertain. The aim of this study was to evaluate the prognostic value of NEK2 in human tumors. Methods: A comprehensive literature search was performed for PubMed, Embase, Web of Science, and CNKI databases, and eligible studies were included based on the inclusion and exclusion criteria. A meta-analysis of the included studies was then carried out. Results: Fifteen studies with 3,280 cancer patients were included in the present meta-analysis. All publications were of moderate to high quality, and had no significant heterogeneity (I 2=46% , P=0.03) or publication bias was discovered. The results showed that a high NEK2 level was associated with shorter overall survival (OS) in patients with various types of cancers (pooled HR=1.72, 95% CI 1.49-2.00, P<0.00001). However, the disease-free survival (DFS) had no significant association with NEK2 level (HR=1.13, 95% CI: 0.29-4.38, P=0.85). In the subgroup analyses, high NEK2 level was correlated with an increased risk of poor OS in patients with hepatocellular carcinoma (HR=1.62, 95% CI: 1.25-2.10, P=0.02) and lung cancer (HR=2.18, 95% CI: 1.40-3.38, P=0.0005). However, other factors, including sample size, follow-up period, HR estimation method, and country, also affect the association between NEK2 expression and OS. Analysis of clinicopathological parameters further showed that increased NEK2 level was correlated with younger age, male gender, better tumor differentiation, and lower number of tumor nodules. Conclusion: The results of this study indicated that increased expression of NEK2 was associated with unfavorable survival of cancer patients and that NEK2 could be used as a prognostic predictor for cancers.

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“…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.…”

Section: Key Proliferative and Angiogenic Pathways Targeted By Deguelinmentioning

confidence: 99%

“…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.…”

Section: Preventing Metastasismentioning

confidence: 99%

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

Varughese

Lam

Marican

et al. 2019

Cancer

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Deguelin is a rotenoid compound that exists in abundant quantities in the bark, roots, and leaves of the Leguminosae family of plants. An analysis of evidence from both in vitro and in vivo studies suggests that deguelin displays potent anticancer activity against multiple cancer types and exhibits chemopreventive potential in Akt‐inducible transgenic mouse models. Deguelin appears to impede carcinogenesis by enhancing cell apoptosis and hindering malignant transformation and tumor cell propagation. Crucial oncogenic pathways likely targeted by deguelin include the epithelial‐to‐mesenchymal transition; angiogenesis‐related pathways; and the phosphoinositide 3‐kinase/Akt, Wnt, epidermal growth factor receptor, c‐Met, and hedgehog signal transduction cascades. This review article provides a comprehensive summary of current preclinical research featuring deguelin as a leading chemotherapeutic and chemopreventive compound, and it highlights the importance of identifying companion molecular biomarkers and performing systemic pharmacokinetic studies for accelerating the process of developing deguelin as a clinical anticancer agent.

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

Cited by 19 publications

References 30 publications

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

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

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

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

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