Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway

Abstract

Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinases downstream of epidermal growth factor receptor revealed that the RAF-MEK-ERK signaling pathway was significantly inhibited. Furthermore, the cellular senescence induced by arctigenin could be reverted by pcDNA-epidermal growth factor receptor. Arctigenin also potently inhibited the growth of tumor xenografts, which was accompanied by the downregulation of epidermal growth factor receptor and induction of senescence. This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway. These data identify epidermal growth factor receptor as a key regulator in arctigenin-induced gallbladder cancer senescence.

Arctigenin induces apoptosis in human hepatoblastoma cells

“…Polyphyllin D induced apoptosis and necrosis in cells in a caspase-dependent manner as we reported previously [11]. Arctigenin also induced apoptosis in lung cancer, breast cancer, gallbladder cancer, hepatocellular carcinoma, and colorectal cancer cells [5][6][7][8][9][10]. We thus examined whether arctigenin similarly induces apoptosis in hepatoblastoma cells through caspase activation.…”

“…It is a component of the herbal medicines, Saikoseikanto, which is often used to treat neurosis in children, chronic tonsillitis, eczema, chronic gastrointestinal disorders, and neurosis in weak constitution, and Kufugedokusan, which is effective against sore throat, tonsillitis, and peritonsillitis. In addition, the anti-tumor effect of arctigenin on cell lines derived from lung cancer, breast cancer, gallbladder cancer, colorectal cancer, and hepatocellular carcinoma cases has been reported, but not on those from hepatoblastomas [5][6][7][8][9][10]. In addition to its anti-tumor effects, arctigenin is thought to possess diverse properties, including anti-influenza, anti-inflammatory/analgesic, and anti-hypertension [12][13][14].…”

“…The results of our experiment indicated that necroptosis occurred in a cell line with the MYCN gene, while apoptosis occurred in a cell line lacking the MYCN gene [11]. Although the pathways mediating the antitumor effect of arctigenin are different in various tumors, apoptosis induction occurs in all tumors [5][6][7][8][9][10]. Exogenous apoptosis is initiated with the detection of an extracellular stress signal by a specific intramembrane/extramembrane receptor [15].…”

“…Arctigenin, the main ingredient of Goboshi, i.e., burdock seeds, has been reported to exhibit antitumor effects against lung cancer, breast cancer, gallbladder cancer, hepatocellular carcinoma, colorectal cancer, etc. [5][6][7][8][9][10]. We examined the anti-tumor effects of arctigenin 1 Pediatric Surgery Department, Fujita Health University, Toyoake, Japan in the hepatoblastoma cell line HUH-6 clone 5 (hereinafter, referred to as HUH-6).…”

Arctigenin induces the apoptosis of primary effusion lymphoma cells under conditions of glucose deprivation

“…Arctigenin, a representative dibenzylbutyrolactone lignin, is an extract from the burdock plant, Arctium lappa, whose seed has traditionally been used in Japanese Kampo medicine for detoxification and inflammation, including in mastitis. Arctigenin has been reported to exhibit many biological functions, such as anticancer, anti-inflammatory (17), antiviral (18,19), immunomodulatory, antioxidant (20), neuroprotective (20) and antidiabetic (21) activities, and has been shown to modulate cell signaling pathways, such as signal transducer and activator of transcription 3 (STAT3) (22), Akt (23,24), NF-κB (24), p38 mitogen-activated protein kinase (p38 MAPK) (25,26) and ERK (24,27). In addition to affecting cell signaling, arctigenin influences ER stress and inhibits or activates the UPR, resulting in apoptosis or protection against ER stress (28)(29)(30).…”