β,β-Dimethylacrylshikonin Induces Mitochondria Dependent Apoptosis through ERK Pathway in Human Gastric Cancer SGC-7901 Cells

Abstract

β,β-Dimethylacrylshikonin, one of the active components in the root extracts of Lithospermum erythrorhizon, posses antitumor activity. In this study, we discussed the molecular mechanisms of β,β-dimethylacrylshikonin in the apoptosis of SGC-7901 cells. β,β-Dimethylacrylshikonin reduced the cell viability of SGC-7901 cells in a dose- and time-dependent manner and induced cell apoptosis. β,β-Dimethylacrylshikonin treatment in SGC-7901 cells down-regulated the expression of XIAP, cIAP-2, and Bcl-2 and up-regulated the expression of Bak and Bax and caused the loss of mitochondrial membrane potential and release of cytochrome c. Additionally, β,β-dimethylacrylshikonin treatment led to activation of caspases-9, 8 and 3, and cleavage of poly (ADP-ribose) polymerase (PARP), which was abolished by pretreatment with the pan-caspase inhibitor Z-VAD-FMK. β,β-Dimethylacrylshikonin induced phosphorylation of extracellular signal-regulated kinase (ERK) in SGC-7901 cells. U0126, a specific MEK inhibitor, blocked the ERK activation by β,β-dimethylacrylshikonin and abrogated β,β-dimethylacrylshikonin -induced apoptosis. Our results demonstrated that β,β-dimethylacrylshikonin inhibited growth of gastric cancer SGC-7901 cells by inducing ERK signaling pathway, and provided a clue for preclinical and clinical evaluation of β,β-dimethylacrylshikonin for gastric cancer therapy.

Statin induces apoptosis of human colon cancer cells and downregulation of insulin-like growth factor 1 receptor via proapoptotic ERK activation

“…EGF stimulation caused a transient activation of ERK1/2, peaking at 15 min and reducing back to basal levels after 40 min, and induced cell proliferation in PC12 cells, while NGF stimulated sustained activation of A B C D ERK1/2 after 15-180 min, which resulted in the differentiation of cells (20). Previously, β,β-dimethylacrylshikonin induced mitochondria-dependent apoptosis through the ERK pathway in human gastric cancer SGC-7901 cells (21). Shen et al (21) suggested that sustained ERK activation induces apoptosis.…”

“…Previously, β,β-dimethylacrylshikonin induced mitochondria-dependent apoptosis through the ERK pathway in human gastric cancer SGC-7901 cells (21). Shen et al (21) suggested that sustained ERK activation induces apoptosis. In this study, a specific inhibitor of MEK blocked β,β-dimethylacrylshikonin-induced ERK activation and apoptosis in SGC-7901 cells (21).…”

“…Shen et al (21) suggested that sustained ERK activation induces apoptosis. In this study, a specific inhibitor of MEK blocked β,β-dimethylacrylshikonin-induced ERK activation and apoptosis in SGC-7901 cells (21). Kim et al showed that glucose deprivation induced adenosine monophosphate-activated kinase (AMPK) and proapoptotic ERK activation in HCT116 cells (22).…”

Activation of JNK/p38 Pathway is Responsible for α-Methyl-n-butylshikonin Induced Mitochondria-Dependent Apoptosis in SW620 Human Colorectal Cancer Cells

“…Zeng Y et al also found that acetylshikonin led to cell apoptosis in human gastric carcinoma cell line SGC-7901 via elevation of Bax /Bcl-2 ratio (Zeng et al, 2009). Recently, we reported that β,β-dimethylacrylshikonin induced mitochondria-dependent apoptosis via ERK1/2 pathway in human gastric cancer SGC-7901 cells (Shen et al, 2012).…”

“…The translocalization of apoptotic proteins from the cytoplasm to the mitochondria membrane leads to cytochrome c release and second mitochondria-derived activator of caspases by a loss of mitochondrial membrane potential (Shimizu et al, 1999). Our previous findings have demonstrated that β,β-dimethylacrylshikonin induces apoptosis via mitochondria pathway in SGC-7901 cells (Shen et al, 2012). In the present study, we showed that MBS down-regulated the expression of Bcl-2 and up-regulated the expression of Bak, and caused the loss of mitochondrial membrane potential in SW620 cells, consistent with activation of the mitochondria-dependent apoptosis.…”