Abstract
Proteins that promote epithelial to mesenchymal transition (EMT) are associated with cancer metastasis. Inhibition of EMT regulators may be a promising approach in cancer therapy. In this study, Thymoquinone (TQ) was used to treat cancer cell lines to investigate its effects on EMT-regulatory proteins and cancer metastasis. We show that TQ inhibited cancer cell growth, migration and invasion in a dose-dependent manner. At the molecular level, TQ treatment decreased the transcriptional activity of the TWIST1 promoter and the mRNA expression of TWIST1, an EMT-promoting transcription factor. Accordingly, TQ treatment also decreased the expression of TWIST1-upregulated genes such as N-Cadherin and increased the expression of TWIST1-repressed genes such as E-Cadherin, resulting in a reduction of cell migration and invasion. TQ treatment also inhibited the growth and metastasis of cancer cell-derived xenograft tumors in mice but partially attenuated the migration and invasion in TWIST1-overexpressed cell lines. Furthermore, we found that TQ treatment enhanced the promoter DNA methylation of the TWIST1 gene in BT 549 cells. Together, these results demonstrate that TQ treatment inhibits TWIST1 promoter activity and decreases its expression, leading to the inhibition of cancer cell migration, invasion and metastasis. These findings suggest TQ as a potential small molecular inhibitor of cancer growth and metastasis.
Highlights
Cancer metastasis is the major characteristic of malignant carcinomas and is common in late stage of cancer
This study investigated the role of TQ on the expression of epithelial to mesenchymal transition (EMT) mediator proteins like Cadherins and Vimentin, and their regulatory transcription factors TWIST1, SNAIL1, SLUG and ZEB1 in metastatic cancer cell lines, as well as tumor model of mice
In order to investigate the TQ effect on the expression of EMT associated proteins, cancer cells were treated with 5 μM of TQ for 6 hours, and total RNA was extracted from cells for quantitative real time PCR
Summary
Cancer metastasis is the major characteristic of malignant carcinomas and is common in late stage of cancer. Despite the great advances of modern medical science in the last century, metastatic tumors are not yet curable. This is partly because of the complex mechanism of metastasis, and the difficulties in developing efficient treatments. EMT allows the cancer cells to acquire invasive properties and to develop migratory and invasive characteristics. These events are facilitated by the down-regulation of cell-cell adhesion molecule E-Cadherin, up-regulation of more plastic mesenchymal proteins such as www.impactjournals.com/oncotarget
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