Cantharidin inhibits cell proliferation and promotes apoptosis in tongue squamous cell carcinoma through suppression of miR-214 and regulation of p53 and Bcl-2/Bax

Abstract

Cantharidin, a type of terpenoid, is a chemical compount secreted by the blister beetle or Mylabris phelarata pallas of the Meloidae family. Cantharidin is known to have good antitumor activity. The present study aimed to investigate the anticancer effect of cantharidin and its possible underlying mechanism using tongue squamous cell carcinoma (TSCC) TCA8113 cells. TCA8113 cells were treated with various concentrations of cantharidin, and the cell viability and cytotoxicity were assessed using MTT and LDH assays, respectively. Flow cytometry was conducted to examine cell apoptosis and colorimetric protease assay was performed to analyze caspase-9/3 activities in TCA8113 cells. qPCR and western blot analysis were used to investigate microRNA-214 (miR-214) expression, as well as the expression of p53, Bcl-2 and Bax proteins in TCA8113 cells. miR-214 and anti-miR-214 were transfected with mimics to examine whether miR-214 expression regulated the anticancer effect of cantharidin on TCA8113 cells and p53, Bcl-2 and Bax protein expression. The anticancer effect of cantharidin significantly inhibited cell proliferation and increased cytotoxicity of TSCC Tca8113 cells in a dose- and time-dependent manner. In addition, cantharidin induced cell apoptosis and activated caspase-9/3 activities of TSCC Tca8113 cells. Cantharidin markedly weakened miR-214 expression level, activated p53 protein expression, and suppressed the Bcl-2/Bax signaling pathway in Tca8113 cells. Downregulation of miR-214 increased p53 protein expression and decreased the Bcl-2/Bax signaling pathway of TSCC Tca8113 cells. However, the overexpression of miR-214 reduced the anticancer effect of cantharidin on the proliferation and apoptosis of TSCC Tca8113 cells, inhibited p53 protein expression, and increased the Bcl-2/Bax signaling pathway. The results suggested that cantharidin is a potential anticancer drug that can be used to regulate the proliferation and apoptosis of human TSCC Tca8113 cells. Additionally, its mechanism may partially be associated with the downregulation of miR-214, upregulation of p53 protein expression and suppression of the Bcl-2/Bax signaling pathway.

Cantharidin suppressed breast cancer MDA-MB-231 cell growth and migration by inhibiting MAPK signaling pathway

“…Based on previous findings of cantharidin as the active constituent of the Chinese medicine Mylabris (8,10–12,14,15,17,20), the possible therapeutic values of cantharidin against breast cancer and underlying pathways associated with this anticancer activity were investigated in this study.…”

“…Recently, cantharidin has received sudden research expansion and has become a major focus in anticancer research. The latest studies have found that cantharidin and its derivatives have potent anticancer activities in various types of cancer, such as hepatoma (9), lung cancer (10), gastric cancer (11), pancreatic cancer (8,12,13), bladder cancer (14,15), epidermoid carcinoma (16), and tongue squamous cell carcinoma (17). Clinical trials have inspiringly shown that cantharidin and its analogs have therapeutic effects against primary hepatoma and advanced stage cases (7,18).…”

“…Cantharidin inhibits PP2A and thereby phosphorylates multiple kinases and activates these kinase-mediated pathways. Consequently, cantharidin has exerted wide roles during tumor growth suppression, including the promotion of cell apoptosis and cell cycle arrest (10,11,14,17), and the induction of DNA damage (10). Cantharidin also inhibits cell migration and invasion through accelerated degradation of matrix metalloproteinase (MMP) (12,20).…”

The FOXD3/miR-214/MED19 axis suppresses tumour growth and metastasis in human colorectal cancer

“…Expression of miR-214 is deregulated in many tumours including pancreatic cancer, melanoma, and hepatocellular carcinoma (Zhang et al , 2010; Penna et al , 2013; Zhang et al , 2015), whereas upregulated in breast cancer by targeting p53 (Wang et al , 2015). The pleiotropic and tumour-specific of miR-214 contributes to various cancer formation and progression via its several target genes including p53 , Bcl-2/Bax , TFAM , EZH2 (Wen et al , 2014; Yang et al , 2014; Tian et al , 2015). Recently, Chen et al (2014) reported that miR-214 negatively regulated liver metastasis in CRC.…”

Cantharidin Overcomes Imatinib Resistance by Depleting BCR-ABL in Chronic Myeloid Leukemia

“…It has been shown that CTD induced G2/M cell cycle arrest and apoptosis in human pancreatic cancer cells, melanoma cells, and colorectal cancer cells (Hsiao et al, 2014; Huang et al, 2011; Li et al, 2010). CTD also inhibited cell growth and promoted mitochondria-dependent apoptosis in cancer cells (Hsia et al, 2014; Kuo et al, 2010; Tian et al, 2015). CTD exerted its anti-tumor effect through inducing DNA damage and inhibiting DNA repair associated proteins in human lung cancer cells, NCI-H460, and human bladder cancer cells (Hsia et al, 2015; Kuo et al, 2015).…”