Thymoquinone inhibits the proliferation and invasion of esophageal cancer cells by disrupting the AKT/GSK‐3β/Wnt signaling pathway via PTEN upregulation

Abstract

Although thymoquinone (TQ) has been reported to exert antitumor activity against various types of human cancers without evident toxicity, limited studies have reported the effects of TQ on esophageal cancer. Here, we showed that TQ induced cell cycle arrest in the G2/M phase and significantly inhibited cell proliferation and invasion. Further investigation of the potential mechanism revealed that TQ increased the levels of p53 and p21 but significantly reduced the expression of Cyclin B1, Cyclin A, and Cyclin E. Moreover, TQ led to a decrease in Bcl-2 and an increase in cleaved caspase-3, cleaved caspase-7, cleaved caspase-9, and Bax, indicating that TQ induced apoptosis by activating the intrinsic mitochondrial apoptosis pathway. Western blotting showed that TQ disrupted the PI3K/AKT pathway by upregulating PTEN, thus modulating GSK-3β activity, increasing β-catenin degradation, and decreasing decreased MMP-2 and MMP-9 levels in Eca109 cells. However, these changes were attenuated by disrupting PTEN function (using a potent inhibitor) or downregulating PTEN expression. In addition, in vivo results showed that the efficacy of TQ as an antitumor agent in a mouse xenograft tumor model. In conclusion, TQ suppressed human esophageal cancer cells proliferation and invasion both in vitro and in vivo and could provide a novel therapeutic approach for esophageal cancer.

<p>MAGOH/MAGOHB Inhibits the Tumorigenesis of Gastric Cancer via Inactivation of b-RAF/MEK/ERK Signaling</p>

“…Cyclin B1, CDK1 and p27 Kip1 were key mediators in cell cycle distribution. [22][23][24] Cyclin B1 played a key role in G2/M phase of cell cycle distribution. 25 Downregulation of CDK1 could induce G2/M arrest, 26 while p27 Kip1 was negatively correlated with cell growth.…”

Recent Findings on Thymoquinone and Its Applications as a Nanocarrier for the Treatment of Cancer and Rheumatoid Arthritis

“…Furthermore, TQ displayed a hyperproliferative effect in rats and also abrogated Fe (III) nitrilotriacetic acid (Fe-NTA) induced oxidative stress [ 63 ]. TQ reduced Cyclin A, Cyclin B1, Cyclin D1 and Cyclin E [ 82 , 83 , 84 , 85 ] expression and increased levels of p21 and p53 [ 86 , 87 ]. TQ is capable of decreasing Bcl-2 and increasing cleaved caspase-3, 9, and 7, and Bax proteins, as well as modulating the expression of microRNA (miRNA) and long non-coding RNAs (lncRNA), acetylation/deacetylation of histone along with methylation/demethylation of DNA, resulting in mitochondrial apoptosis induction [ 61 , 63 , 88 , 89 ].…”

“…TQ is capable of decreasing Bcl-2 and increasing cleaved caspase-3, 9, and 7, and Bax proteins, as well as modulating the expression of microRNA (miRNA) and long non-coding RNAs (lncRNA), acetylation/deacetylation of histone along with methylation/demethylation of DNA, resulting in mitochondrial apoptosis induction [ 61 , 63 , 88 , 89 ]. TQ also halts the PI3K/AKT signaling pathway by upregulating PTEN, thus interfering with GSK-3β activity, enhancing β-catenin degradation, and decreasing MMP-9 and MMP-2 levels in esophageal cancer cells (Eca109 cells) [ 83 ]. MicroRNA-34a (miR-34a) expression is vital to cancer development and metastasis [ 90 ], and its expression is reduced by TQ in human metastatic breast cancers (MBC) compared to normal breast tissues [ 91 ].…”

Relationship between ENO1 and Metastasis Risk and Prognosis in Esophageal squamous cell carcinoma

“…According to different ways of signal transduction by Wnt protein, Wnt signal transduction can be divided into the canonical Wnt signal pathway and the non-canonical Wnt signaling pathway. Some studies have demonstrated that the Wnt signal pathway is involved in proliferation and migration of ESCC [29][30][31] . In recent years, studies have found that both the canonical and the non-canonical Wnt signal pathways are involved in the induction of EMT.…”