Wogonin induces Beclin-1/PI3K and reactive oxygen species-mediated autophagy in human pancreatic cancer cells

Abstract

Wogonin is considered to be an inhibitor of myeloid cell leukemia 1 and B-cell lymphoma 2, and a potential antitumor drug due to its ability to induce apoptosis in certain cancer cells; however, few previous studies have reported on wogonin-induced autophagy. The aim of the present study was to investigate the influence of wogonin on autophagy in human pancreatic cancer cells (HPCCs), elucidate its mechanism, and identify strategies to increase its effectiveness as an anti-cancer treatment. HPCCs were treated with wogonin and autophagy was detected in the cells. The mechanism of wogonin-related autophagy was investigated, and the antioxidant N-acetyl-L-cysteine (NAC) was used to assess the role of reactive oxygen species (ROS) in wogonin-related autophagy. The results demonstrated that wogonin may induce autophagy by activating the Beclin-1/phosphatidylinositol-3-kinase and ROS pathways in HPCCs, and may enhance ROS generation, followed by the activation of the AKT/ULK1/4E-BP1/CYLD pathway and inhibition of the mammalian target of rapamycin signaling pathway. The incubation of HPCCs with wogonin and the antioxidant NAC, revealed that the effects of wogonin-enhanced ROS generation on autophagy-related molecules were inhibited, contributing to the inhibition of autophagy and increasing the cell death ratio through apoptosis activation in HPCCs. These studies suggest that autophagy activation, via the ROS pathway, by the antitumor drug wogonin in HPCCs may partially reduce the antitumor effects of the drug, and that the antioxidant NAC may enhance the antitumor effectiveness of wogonin via the inhibition of ROS-enhanced autophagy and the subsequent promotion of apoptosis. Therefore, the present research suggests that wogonin combined with NAC may be a novel combination therapy for clinical pancreatic cancer therapy trials.

Expression of autophagy-associated proteins in papillary thyroid carcinoma

“…The human Beclin-1 gene is located on chromosome 17q21. In human pancreatic cancer cells, wogonin is able to activate Beclin-1 and the phosphoinositide 3-kinase (PI3K) signaling pathway, inducing reactive oxygen species-mediated autophagy (21). Beclin-1 also serves a role in the occurrence and development of tumors by regulating autophagy.…”

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

“…It also induces cell cycle arrest in human colorectal cancer HCT-116, NSCLC A549, chronic myelogenous leukemia imatinib-resistant K562, and ovarian cancer A2780 cells [716,[718][719][720]. Besides, wogonin induces autophagy in human pancreatic cells Panc-1 and Colo-357, and nasopharyngeal carcinoma NPC-TW076 and NPC-TW039 cells [721,722]. However, inhibition of autophagy promotes wogonin-induced apoptosis in human nasopharyngeal carcinoma NPC-TW076 and NPC-TW039 cells [722].…”

“…ER stress markers and downstream pathways are also activated following wogonin treatment in human leukemia HL-60 and osteosarcoma U2OS cells, including IRE1α, PERK-eIF2α, ATF-6, CHOP, GRP94 and GRP78 [714,728]. Wogonin also enhances ROS production in human glioma U251 and U87, pancreatic cancer Panc-1 and Colo-357, and NSCLC A549 cells [711,721,729]. Moreover, it inhibits cell growth and induces apoptosis through NF-κB suppression in Epstein-Barr virus-positive lymphoma cells [730], and suppresses cell proliferation and invasion through NF-κB/Bcl-2 and EGFR pathways in human hepatocellular carcinoma HepG2 and Bel-7402 cells [717].…”

TCS2 Increases Olaquindox-Induced Apoptosis by Upregulation of ROS Production and Downregulation of Autophagy in HEK293 Cells

“…Nevertheless, the current results revealed that pretreatment with NAC efficiently reduced ROS generation and blocked olaquindox-induced autophagy as well ( Figure 4 ). However, there are a number of reports related to inhibition of ROS-mediated autophagy [ 31 , 32 ]. In short, we speculate that ROS might play an upstream role in olaquindox-induced autophagy.…”