Mitochondrial ROS contribute to oridonin-induced HepG2 apoptosis through PARP activation

Abstract

Oridonin, the main active constituent of Rabdosia rubescens, is known to exert antitumor activity via the induction of apoptosis in numerous types of human cancer cells. However, the underlying regulatory mechanisms of mitochondrial ROS in oridonin-induced HepG2 apoptosis remain largely unknown, due to limitations of subcellular imaging resolution. Previously, it has been suggested that mitochondria serve a potential role in sensing and signaling cellular redox changes in vital biological processes such as cell death and the abiotic stress response, based on studies involving the mitochondrial-targeted redox-sensitive green fluorescent protein (GFP). To address this, a mitochondrial-targeted Grx1-roGFP2 (mtGrx1-roGFP2) biosensor was implemented to monitor real-time mitochondrial redox changes of HepG2 cells in response to either H2O2/DTT or oridonin/SS31 treatment. It was determined that oridonin caused a perturbation in mitochondrial redox status, which in turn contributed to oridonin-induced apoptosis. Furthermore, a novel mechanism underlying the regulation of mitochondrial redox changes in oridonin-induced HepG2 apoptosis, presumably dependent on PARP cleavage, was proposed. In conclusion, the present study provides evidence in support of mitochondrial redox changes as a potential mediator in the apoptotic activities of oridonin in HepG2 cells, which provides insight into the molecular mechanisms by which mitochondrial redox signaling regulates oridonin-induced apoptosis in cancer therapy, and the development of mitochondria-specific oridonin as a promising novel anticancer therapeutic strategy.

Oridonin inhibits the migration and epithelial‐to‐mesenchymal transition of small cell lung cancer cells by suppressing FAK‐ERK1/2 signalling pathway

“…As a high concentration of oridonin was reported to induce apoptosis, therefore, to investigate whether lower concentrations of oridonin could induce apoptosis in H1688 cells, some experiments were performed. First, as demonstrated in Figure 2A, the result of Hoechst staining showed that the percentage of apoptotic cells characterized by nuclear condensation and fragmentation was approximately 4.88 ± 1.22% in the control group (Figure 2B).…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Oridonin inhibits cell growth and induces apoptosis through ER stress and ASK1/JNK signaling pathways in human hepatocellular carcinoma Huh6 cells [559]. Besides, the mitochondrial redox change is proved to be a potential mediator for the pro-apoptosis effect of oridonin [565]. The anti-proliferative effect of oridonin is also shown to be associated with mitochondrial-mediated apoptosis, which is characterized by mitochondrial membrane potential reduction, subsequent cytochrome c release, PARP, caspase-3 and -9 activation, and decreased Bcl-2/Bax ratio [551,565,574,575].…”

“…Oridonin induces apoptosis in human hepatocellular carcinoma HepG2 and Huh6, oral squamous cell carcinoma WSU-HN4, WSU-HN6 and CAL27, and laryngeal cancer HEp-2 cells [550,559,561,565]. It also induces G2/M cell cycle arrest in human oral squamous cell carcinoma WSU-HN4, WSU-HN6 and CAL27, gastric cancer SGC-7901, prostate cancer PC-3 and DU-145, and breast cancer MCF-7 cells [555,561,566,567].…”

“…Besides, the mitochondrial redox change is proved to be a potential mediator for the pro-apoptosis effect of oridonin [565]. The anti-proliferative effect of oridonin is also shown to be associated with mitochondrial-mediated apoptosis, which is characterized by mitochondrial membrane potential reduction, subsequent cytochrome c release, PARP, caspase-3 and -9 activation, and decreased Bcl-2/Bax ratio [551,565,574,575]. Oridonin also inhibits cell proliferation through bone morphogenetic protein 7 (BMP7)/p38 MAPK/ p53 pathway in human colorectal cancer HCT-116 and SW-620 cells [553,576,577], and induces apoptosis via hydrogen peroxide (H 2 O 2 ) production and glutathione depletion in human colorectal cancer SW-1116 cells [578].…”

Involvement of Glutathione Depletion in Selective Cytotoxicity of Oridonin to p53-Mutant Esophageal Squamous Carcinoma Cells

“…Oridonin, an active diterpenoid compound extracted and purified from Rabdosia rubescens, has great effects on suppressing the proliferation of esophageal, gastric, liver, and colon cancer cells (6)(7)(8). Previous shreds of evidence have shown that oridonin-mediated apoptosis involves multiple proteins and pathways, such as protein kinase B (AKT), the nuclear factor-kappa B (NF-κB) and mitochondrial redox signaling pathway (9)(10)(11). However, the molecular target of the anti-tumor effect of oridonin has not been fully elucidated, which limits the further clinical application of oridonin.…”