Ginsenoside Rh2 Inhibited Proliferation by Inducing ROS Mediated ER Stress Dependent Apoptosis in Lung Cancer Cells

Abstract

Key words ginsenoside Rh2; lung cancer; apoptosis; reactive oxygen species; endoplasmic reticulum stress Followed by serial biological steps including hyperplasia, metaplasia, dysplasia and in situ carcinoma, similar to other cancers, lung cancer eventually develops its malignancy marked by strong proliferative capacity which is characterized by resistance to apoptosis. 1) Nowadays, lung cancer is still among the top common cancers worldwide. According to the records, lung cancer composes 12.7% of cancer and 18.2% of cancer related death.2) Though the multiple therapies including surgery, radiotherapy and chemotherapy are more and more widely applied to patients, the prognosis of lung cancer is still poor due to its malignant nature. Non-small cell lung cancer (NSCLC) takes approximately 85% of lung cancer cases with less than 20% 5-year survival rate.3) Seeking and identifying new drugs inducing apoptosis may provide us new insight into prevention and treatment of lung cancer.As one of the vital organelles in eukaryotic cells, endoplasmic reticulum (ER) is responsible for directing correct protein folding, calcium homeostasis and lipid metabolism. 4) However, under certain physiological and pathological conditions, the normal functions of ER were impaired by multiple extra-or intra-cellular stimuli, which is referred as ER stress.5) Reactive oxygen species (ROS) is considered as one of the stimuli inducing ER stress. This phenotype is called ROS-mediated ER stress. 6) Many anticancer agents such as chemotherapeutic drugs are believed to induce apoptosis by generating excessive intracellular ROS which is related with unfolded protein response (UPR) in ER to induce ER stress. 7) Numerous investigations supposed that ROS-mediated ER stress could further promote cell apoptosis by activating CCAAT/enhancer binding protein (C/EBP) homologous protein CHOP signaling pathway.8) As a pre-apoptotic factor, CHOP is suggested to activate caspase cascade by inducing cleavage of caspase-12 (rodents) 9) or caspase-4 (human). 10)In recent decades, natural products gradually become new alternatives besides regular therapies. With a long history in traditional medicine in East Asia, ginseng (Panax quinquefolius) is now a very popular herb as medicine or food supplement in the world. 11) Extracted from roots of ginseng, ginsenosides are the main effective components.12) It was suggested in the previous study that among the ginsenosides, ginsenoside Rh2 (G-Rh2, first isolated by Shizuo Odashima 13) ) exhibited various biological and pharmacological activities including anti-inflammation, anti-diabetes and anti-cancer. 14-17)A recent report supposed that G-Rh2 induced colorectal cancer cell apoptosis by inducing excessive intracellular ROS generation.18) Thus, ROS-mediated ER-stress induced apoptosis attracted our attention in investigating gensenoside Rh2's mechanism of anti-proliferation.In this present study, we showed G-Rh2 inhibited proliferation of lung cancer cells by inducing apoptosis. Furthermore, whether ROS-mediated ER-s...

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“…Reactive oxygen species contribute to ER stress, a process called ROS-mediated ER stress. When mitochondrial dysfunction occurs, increased ROS production results in unfolded protein response in the ER, thus inducing ER stress, which if sustained, can lead to apoptosis [ 39 , 40 ]. Iwasawa et al suggested that when mitochondrial dysfunction occurs, the mitochondrial fission protein, fission 1 homologue (Fis1), serves to transmit an apoptotic signal from the mitochondria to the ER by interacting with Bap31 at the ER [ 41 ].…”

Pseudo‑Ginsenoside Rh2 induces A549 cells apoptosis via the Ras/Raf/ERK/p53 pathway

“…However, during the later stages of cancer, ROS accumulation induces p53 expression, which in turn causes cell cycle arrest at the G2/M phase, DNA fragmentation and apoptosis ( 38 ). It has been reported that G may induce cell cycle arrest or cell death by increasing ROS release in cancer cells ( 39 , 40 ). ROS has also been reported to be a mediator of ERK-induced cell death ( 41 , 42 ); specifically, elevated ROS results in sustained ERK activity, which in turn causes enhanced p53 expression ( 43 ).…”

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“…Ginsenoside Rg3 can also modulate the tumor environment through inhibiting angiogenesis and enhancing anti-tumor immune responses [241]. Moreover, ginsenoside Rh2 exhibits anti-tumor activity in human NSCLC H1299 cells and H1299 xenograft mice, through the induction of ROS-mediated ER-stress-dependent apoptosis [242]. It also suppresses cell proliferation and migration, and induces cell cycle arrest in human hepatocellular carcinoma HepG2 and Hep3B cells, and inhibits tumor growth in HepG2 xenograft mice [243].…”