Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression

Wang, Jie; Cai, Han; Xia, Yunlong; Wang, Shiying; Xing, LiKai; Chen, Chao; Zhang, Yong; Xu, Jie; Yin, Peihao; Jiang, Yiming; Zhao, Ronghua; Zuo, Qingshong; Chen, Teng

doi:10.18632/oncotarget.24157

Cited by 27 publications

(23 citation statements)

References 38 publications

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“…We have observed the inhibition of GSK3α and β-catenin by the activation of a destructive complex and further enhancing the deregulation of c-Myc and cyclin D1, stimulating cell death. In the current study, our results confirm strophanthidin's importance in the inhibition of Wnt/βcatenin signaling, and this activity was correlated with earlier reports suggesting that bufalin inhibits Wnt/β-catenin signaling in gastric cancer cells to induce apoptosis (69). However, this is the first report to show the role of strophanthidin in Wnt/βcatenin signaling and its downstream target genes.…”

Section: O21supporting

confidence: 92%

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

2020

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Lung cancer is the most prevalent in cancer-related deaths, while breast carcinoma is the second most dominant cancer in women, accounting for the most number of deaths worldwide. Cancers are heterogeneous diseases that consist of several subtypes based on the presence or absence of hormone receptors and human epidermal growth factor receptor 2. Several drugs have been developed targeting cancer biomarkers; nonetheless, their efficiency are not adequate due to the high reemergence rate of cancers and fundamental or acquired resistance toward such drugs, which leads to partial therapeutic possibilities. Recent studies on cardiac glycosides (CGs) positioned them as potent cytotoxic agents that target multiple pathways to initiate apoptosis and autophagic cell death in many cancers. In the present study, our aim is to identify the anticancer activity of a naturally available CG (strophanthidin) in human breast (MCF-7), lung (A549), and liver cancer (HepG2) cells. Our results demonstrate a dose-dependent cytotoxic effect of strophanthidin in MCF-7, A549, and HepG2 cells, which was further supported by DNA damage on drug treatment. Strophanthidin arrested the cell cycle at the G2/M phase; this effect was further validated by checking the inhibited expressions of checkpoint and cyclin-dependent kinases in strophanthidin-induced cells. Moreover, strophanthidin inhibited the expression of several key proteins such as MEK1, PI3K, AKT, mTOR, Gsk3α, and β-catenin from MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling. The current study adequately exhibits the role of strophanthidin in modulating the expression of various key proteins involved in cell cycle arrest, apoptosis, and autophagic cell death. Our in silico studies revealed that strophanthidin can interact with several key proteins from various pathways. Taken together, this study demonstrates the viability of strophanthidin as a promising anticancer agent, which may serve as a new anticancer drug.

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Section: O21supporting

confidence: 92%

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

2020

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“…Few recent studies have reported the role of AHNAK in GC. However, studies have indicated that the AHNAK gene was closely related to the Wnt signaling pathway [12,16], and the Wnt signaling pathway was suggested to be closely associated with the development of GC [17,18]. We have shown that the AHNAK gene was a direct target gene of miR-93-5p in GC.…”

Section: Down-regulation Of Mir-93-5p Inhibits Activation Of the Wnt mentioning

confidence: 80%

“…It is also documented that Wnt signaling pathway also known as Wnt/β-catenin signaling pathway since it can regulate β-catenin protein levels therefore activating the Wnt, which could regulate Frizzled-1/β-catenin signaling pathway [30]. Dysregulation of Wnt signaling is observed in various human disease including GC, which is usually associated with the development stage of human cancers [17,18,31,32]. Besides miR-93-5p, other miRNAs including miR-139-5p may regulate Wnt-related factors, which could directly target the Wnt/β-catenin signaling pathways related Wnt-1 and suppress the expression of Wnt-1 and β-catenin [33].…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: MicroRNA-93-5p promotes epithelial-mesenchymal transition in gastric cancer by repressing tumor suppressor AHNAK expression

et al. 2020

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Background: Gastric cancer (GC) is a common cause of cancer-related mortality worldwide, and microRNAs (miRNAs) have been shown to play an important role in GC development. This study aims to explore the effect of microRNA-93-5p (miR-93-5p) on the epithelial-mesenchymal transition (EMT) in GC, via AHNAK and the Wnt signaling pathway. Methods: Microarray-based gene expression analysis was performed to identify GC-related differentially expressed miRNAs and genes. Then the expression of the miR-93-5p was examined in GC tissues and GC cell lines. The targeting relationship between miR-93-5p and AHNAK was verified by a dual luciferase reporter gene assay. In an attempt to ascertain the contributory role of miR-93-5p in GC, miR-93-5p mimic or inhibitor, as well as an AHNAK overexpression vector, were introduced to HGC-27 cells. HGC-27 cell migration and invasive ability, and EMT were assayed using Transwell assay and western blot analysis. Regulation of the Wnt signaling pathway was also assessed using TOP/FOP flash luciferase assay. Results: miR-93-5p was highly expressed in GC tissue samples and cells. Notably, miR-93-5p could target and negatively regulate AHNAK. Down-regulation of miR-93-5p or overexpression of AHNAK could suppress the migration and invasion abilities, in addition to EMT in GC cells via inactivation of the Wnt signaling pathway. Conclusion: Taken together, downregulation of miR-93-5p attenuated GC development via the Wnt signaling pathway by targeting AHNAK. These findings provide an enhanced understanding of miR-93-5p as a therapeutic target for GC treatment.

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“…Bufalin can attenuate transforming growth factor-β (TGF-β)-induced upregulation of N-cadherin, vimentin, and Snail while downregulating E-cadherin by targeting hypoxia-inducible factor-1α (HIF-1α) [76]. In addition, the regulating of motility and invasiveness of cancer cells may be related to the PI3K/AKT/mTOR pathway [76, 81], Wnt/β-catenin pathway [66, 77], Hedgehog signaling pathway [67, 82], and etc.…”

Section: Molecular Mechanisms Of Anti-tumor Activitymentioning

confidence: 99%

New therapeutic aspects of steroidal cardiac glycosides: the anticancer properties of Huachansu and its main active constituent Bufalin

et al. 2019

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Aim of the review In the past decade, increasing research attention investigated the novel therapeutic potential of steroidal cardiac glycosides in cancer treatment. Huachansu and its main active constituent Bufalin have been studied in vitro, in vivo and clinical studies. This review aims to summarize the multi-target and multi-pathway pharmacological effects of Bufalin and Huachansu in the last decade, with the aim of providing a more comprehensive view and highlighting the recently discovered molecular mechanisms. Results Huachansu and its major derivative, Bufalin, had been found to possess anti-cancer effects in a variety of cancer cell lines both in vitro and in vivo. The underlying anti-cancer molecular mechanisms mainly involved anti-proliferation, apoptosis induction, anti-metastasis, anti-angiogenesis, epithelial–mesenchymal transition inhibition, anti-inflammation, Na + /K + -ATPase activity targeting, the steroid receptor coactivator family inhibitions, etc. Moreover, the potential side-effects and toxicities of the toad extract, Huachansu, and Bufalin, including hematological, gastrointestinal, mucocutaneous and cardiovascular adverse reactions, were reported in animal studies and clinic trails. Conclusions Further research is needed to elucidate the potential drug–drug interactions and multi-target interaction of Bufalin and Huachansu. Large-scale clinical trials are warranted to translate the knowledge of the anticancer actions of Bufalin and Huachansu into clinical applications as effective and safe treatment options for cancer patients in the future.

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Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression

Cited by 27 publications

References 38 publications

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

RETRACTED ARTICLE: MicroRNA-93-5p promotes epithelial-mesenchymal transition in gastric cancer by repressing tumor suppressor AHNAK expression

New therapeutic aspects of steroidal cardiac glycosides: the anticancer properties of Huachansu and its main active constituent Bufalin

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