Tanshinone I induces apoptosis and pro-survival autophagy in gastric cancers

Shin

et al. 2018

Phytotherapy Research

Though Tanshinone I (Tan I), a phenolic compound from Salvia miltiorrhiza, is known to have anticancer activity in several cancers, its anticancer mechanisms are not fully understood in colon cancer cells. Thus, in the present study, the underlying molecular mechanism of Tan I was explored in HCT116 and HT29 colorectal cancer cells (CRCs). Here, Tan I suppressed viability in HCT116 and HT29 cells in a time- and dose-dependent manner. Also, Tan I increased the number of terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL)-positive cells and sub-G1 population in HCT116 and HT29 cells. Consistently, Tan I cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) and caspase-8, caspase-3, attenuated the expression of Bid and activated tBid as a caspase-8 substrate and activated phosphorylation of p38 MAPK in HCT116and HT29 cells. Of note, Tan I generated reactive oxygen species (ROS) and conversely an ROS scavenger, N-acetyl- -cysteine, reversed ROS production, PARP cleavage, caspase-3 activation, and p38 MAPK phosphorylation induced by Tan I in HCT116 cells. Furthermore, p38 MAPK inhibitor SB203580 reduced cytotoxicity, increase of TUNEL-positive cells, cleavages of PARP and caspase-3 induced by Tan I in HCT116 cells. Overall, our findings for the first time suggest that ROS-dependent activation of p38 MAPK and caspase-3 is critically involved in Tan I induced apoptosis in CRCs as a potent anticancer agent.

Section: Discussionmentioning

confidence: 99%

Reactive oxygen species‐mediated phosphorylation of p38 signaling is critically involved in apoptotic effect of Tanshinone I in colon cancer cells

Shin

et al. 2018

Phytotherapy Research

“…In GC, Jing et al first reported that TSN induced apoptosis and growth inhibition in vitro and in vivo . Subsequent research showed that TSN could reverse the malignant phenotype of GC cells and induce pro-survival autophagy in GC cells (22,23). In accordance with these studies, our research found that TSN inhibited the proliferation and migration ability of SGC-7901 cells in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Tanshinone IIA suppresses gastric cancer cell proliferation and migration by downregulation of FOXM1

Wang

et al. 2017

Oncology Reports

Tanshinone IIA (TSN) exhibits a variety of anticancer effects. However, whether it inhibits gastric cancer (GC) cell proliferation and migration and the mechanism remain unclear. In the present study, different concentrations of TSN were co-incubated with SGC-7901 cells. The pcDNA-FOXM1 or FOXM1-siRNA plasmid was transfected into cells before treatment with 5 µg/l TSN. The proliferation and migration abilities of the SGC-7901 cells were tested by MTT and wound healing assays. Western blotting was used to investigate the expression levels of P21, Ki-67, PCNA, MMP-2, MMP-9 and FOXM1. We found that compared with the control, the proliferation and migration abilities of the SGC-7901 cells were decreased after incubation with different concentrations of TSN in a dose-dependent manner (p<0.01). Moreover, the expression levels of Ki-67, PCAN, MMP-2, MMP-9 and FOXM1 were decreased, and P21 was increased in the TSN-treated SGC-7901 cells (p<0.01). In addition, downregulation of FOXM1 by FOXM1-siRNA had the same effect as TSN on SGC-7901 cells, and overexpression of FOXM1 partly abrogated TSN-mediated inhibition of SGC-7901 cell proliferation and migration. These results suggested that TSN inhibits SGC-7901 cell proliferation and migration by downregulation of FOXM1.

“…Cell viability was detected using cell counting kit 8 (CCK) assay [15]. Cells exposed to media with different pH values (6.0 and 7.4) were inoculated in 96-well culture plates at a density of 4×10 3 per well.…”

Section: Cck8 Assay For Cell Viabilitymentioning

confidence: 99%

FOXO3 Inhibits Human Gastric Adenocarcinoma (AGS) Cell Growth by Promoting Autophagy in an Acidic Microenvironment

Gao

Sun

et al. 2018

Cell Physiol Biochem

Background/Aims: Previous studies have shown that FOXO3, a member of the forkhead box O (FOXO) family, regulates autophagy in various cells. To date, whether the induction of autophagy in gastric cancer (GC) cells is triggered by an acidic microenvironment is unclear. Little is known about the relationship between FOXO3 and acidic microenvironments in GC. The aims of our study were to investigate the roles of FOXO3 and the acidic microenvironment in autophagy and to determine how FOXO3 and the acidic microenvironment regulate GC cell growth through autophagy. Methods: We cultured human gastric adenocarcinoma (AGS) cells in media with different pH values in vitro, transfected the cells with FOXO3a plasmids and then detected autophagy in the cells under different conditions. In addition, we also performed cell counting kit 8 (CCK8), wound and cell invasion assays to test cell viability and invasion, respectively. We employed real-time PCR, western blotting and mRFP-GFP-LC3 vectors to detect the expression of various autophagy indicators. Results: We found that cells treated with FOXO3 and exposed to an acidic microenvironment displayed suppressed growth compared with control cells. We also found that the protein expression levels of several autophagy makers, such as LC3I, LC3II and Beclin-1, were higher in FOXO3 plasmid-transfected AGS cells cultured in an acidic microenvironment than in control cells, while P62 protein expression levels were clearly decreased in FOXO3 plasmid-transfected cells compared with control cells. Moreover, we observed autophagic flux in AGS cells overexpressing FOXO3 and exposed to low pH conditions. Conclusion: These findings suggest that FOXO3 inhibits AGS cell growth by promoting autophagy in an acidic microenvironment. Furthermore, the results showed that anticancer therapies targeting FOXO3 and low pH conditions may be useful in the treatment of GC.