Abstract
Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.
Highlights
To determine the non-toxic concentrations of ovalitenone to be used in the following experiments, human NSCLC H460 and A549 cells were treated with various concentrations of ovalitenone (0–200 μM) for 24 h, and cell viability was measured by 3-[4,5-dimethylthiazol2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) assay
The results show that ovalitenone at concentrations of 0–200 μM had no effect on cell proliferation in H460 and A549 cells at 24 h (Figure 1c,d); the rate of proliferation of the treated cells was significantly decreased in a dose-dependent manner at concentrations of 50 to 200 μM at 48 h, while ovalitenone at concentrations of 10 to
The results indicate that ovalitenone suppressed epithelial-to-mesenchymal transition (EMT) and AKT/mammalian target of rapamycin (mTOR) signals, which are important controllers of cancer cell migration, invasion, and metastasis (Figure 7)
Summary
Lung cancer is one of the most significant human cancers and continues to be the leading cause of cancer deaths globally [1]. Most cancer deaths are caused by cancer metastasis, accounting for approximately 90% of all cancer deaths. Cancer metastasis is a molecular process that involves the spread of cancer cells from a primary tumor to a different site of the body through the blood and lymphatic vessels [2]. Cancer cells must gain their migratory and invasive phenotypes, and they do this through several mechanisms, such as epithelial-to-mesenchymal transition (EMT), whereby cells decrease the apical–basal polarity and switch their pattern and type of adhesion molecules. The EMT process is known for augmenting the cell dissemination potential [3]
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