Potent effects of dioscin against hepatocellular carcinoma through regulating TP53‐induced glycolysis and apoptosis regulator (TIGAR)‐mediated apoptosis, autophagy, and DNA damage

Abstract

Background and purpose: Dioscin shows potent effects against cancers. We aimed to elucidate its pharmacological effects and mechanisms of action on hepatocellular carcinoma (HCC) in vivo and in vitro.Experimental approach: Effects of dioscin were investigated in SMMC7721 and HepG2 cells, diethylnitrosamine-induced primary liver cancer in rats, and cell xenografts in nude mice. Isobaric tags for relative and absolution quantitation (iTRAQ)based proteomics was used to find dioscin's targets and investigate its mechanism.Key results: In SMMC7721 and HepG2 cells dioscin markedly inhibited cell proliferation and migration, induced apoptosis, autophagy, and DNA damage. It inhibited DEN-induced primary liver cancer in rats, markedly changed body weights and restored levels of α fetoprotein, alanine transaminase, aspartate transaminase, γ-glutamyltransferase, alkaline phosphatase, and Ki67. It also inhibited growth of xenografts in mice. In SMMC7721 cells, 191 differentially expressed proteins were found after dioscin, based on iTRAQ-based assay. TP53-inducible glycolysis and apoptosis regulator (TIGAR) was identified as being significantly down-regulated by dioscin. Dioscin induced cell apoptosis, autophagy, and DNA damage via increasing expression levels of p53, cleaved PARP, Bax, cleaved caspase-3/9, Beclin-1, and LC3 and suppressing those of Bcl-2, p-Akt, p-mammalian target of rapamycin (mTOR), CDK5, p-ataxia telangiectasia-mutated gene (ATM). The transfection of TIGAR siRNA into SMMC7721 cells and xenografts in nude mice further confirmed that the potent activity of dioscin against HCC is evoked by adjusting TIGAR-mediated inhibition of p53, Akt/mTOR, and CDK5/ATM pathways. Conclusions and implications:The data suggest that dioscin has potential as a therapeutic, and TIGAR as a drug target for treating HCC.

The Effect of TIGAR Knockdown on Apoptotic and Epithelial‐Mesenchymal Markers Expression in Doxorubicin‐Resistant Non‐Small Cell Lung Cancer A549 Cell Lines

“…A recent study has demonstrated that dioscin, a natural steroid saponin, decreased the expression levels of TIGAR and induced cell apoptosis of hepatocellular carcinoma in vitro and in animal model through the involvement of upregulating Bax, caspase-3, 9, PARP, and downregulating Bcl-2 expression. [16] Similar results have been obtained with decrease of TIGAR protein in MCF-7 cell lines. [45] In our study, the downregulation of intact 116 kDa PARP content could reflect a decrease in the capability to repair DNA damage in TIGAR depleted A549-Dox cells in comparison to A549-Dox line.…”

“…[11] Studies have shown that metastasis, the major cause of the deaths at cancer, is directly related to the mesenchymal properties of tumor cells. [12,13] Although the biology of TIGAR has been studied in apoptosis and autophagy in detail, [8,[14][15][16] the role of TIGAR in EMT of lung cancer cells is scarcely reported, and the participation of TIGAR in Dox-resistance of lung cancer cell is yet to be elucidated. Therefore, this study aimed to reveal the role of TIGAR protein in the development of doxorubicin resistance of A549 lung carcinoma cells (A549/ DOX).…”

Licorice Ameliorates Cisplatin-Induced Hepatotoxicity Through Antiapoptosis, Antioxidative Stress, Anti-Inflammation, and Acceleration of Metabolism

“…November 2020 | Volume 11 | Article 563750 activated in the liver and can regulate the transcription of downstream genes, including Bcl-2 and Bax (Mao et al, 2019b). Bcl-2, an antiapoptotic factor, can inhibit apoptosis and promote cell growth by binding to the proapoptotic factor Bax (Willis et al, 2003).…”

“…Apoptosis, oxidative stress, and inflammatory responses were evident after treatment with CP ( Rehman et al, 2014 ), which was also confirmed by our results of network pharmacology. p53 can be activated in the liver and can regulate the transcription of downstream genes, including Bcl-2 and Bax ( Mao et al, 2019b ). Bcl-2, an antiapoptotic factor, can inhibit apoptosis and promote cell growth by binding to the proapoptotic factor Bax ( Willis et al, 2003 ).…”

Antitumor effects of aconitine in A2780 cells via estrogen receptor β‑mediated apoptosis, DNA damage and migration

“…Traditional chinese medicines have been used to treat cancer for thousands of years, using a large collection of biologically active products (18)(19)(20)(21). natural compounds from medicinal plants, including dioscin and berberine, have potent effects against various types of cancer (22)(23)(24)(25)(26)(27)(28); it is reported that berberine inhibited human cervical carcinoma Hela cells and dioscin induced dna damage and activated mitochondrial signal pathway in human a549, nci-H446 and nci-H460 cancer cell lines (29,30). additionally, some natural products, including genistein and daidzein, have been reported to inhibit migration, invasion and proliferation of oVca cells (31).…”