Abstract
Celastrol, a triterpene isolated from the root of traditional Chinese medicine Thunder of God Vine, possesses anti-cancer and anti-inflammatory activity to treat rheumatoid disease or as health product. Necroptosis is considered as a new approach to overcome chemotherapeutics resistance. However, whether celastrol exerts necroptosis leading to gastric cancer cell death is still unclear. Here, for the first time we showed that celastrol induced necroptosis in HGC27 and AGS gastric cancer cell lines. More importantly, celastrol down-regulated biglycan (BGN) protein, which is critical for gastric cancer migration and invasion. Furthermore, celastrol activated receptor-interacting protein 1 and 3 (RIP1 and RIP3) and subsequently promoted the translation of mixed-lineage kinase domain-like (MLKL) from cytoplasm to plasma membrane, leading to necroptosis of gastric cancer cell, which was blocked by over-expression BGN. In addition, celastrol suppressed the release of pro-inflammatory cytokines TNF-α and IL-8 in HGC27 and AGS cells, which was reversed by over-expression BGN. Taken together, we identified celastrol as a necroptosis inducer, activated RIP1/RIP3/MLKL pathway and suppressed the level of pro-inflammatory cytokines by down-regulating BGN in HGC-27 and AGS cells, which supported the feasibility of celastrol in gastric cancer therapy.
Highlights
Gastric cancer is a common malignant tumor of digestive system worldwide, and its incidence rate is high around the world, especially in eastern Asia [1,2,3]
It was reported that natural compounds such as matrine [36], tanshinone IIA [37], shikonin [38], induced cancer cell death by necroptosis
Celastrol inhibited the growth of gastric cancer cells [39], whether necroptosis participated in the event of celastrol-induced cell death is unknown
Summary
Gastric cancer is a common malignant tumor of digestive system worldwide, and its incidence rate is high around the world, especially in eastern Asia [1,2,3]. Clinical data revealed the detection rate of early gastric cancer is very low, so most patients have reached the advanced stage because of symptoms. Chemotherapy and radiotherapy are common therapeutic strategies [4]. The response rate to the chemotherapeutic drugs is only between 20% and 40% [5]. Resistance to cell apoptosis is a major obstacle in gastric cancer chemotherapy. Application of anticancer agents targeting non-apoptitic cell death pathways may be a novel anticancer strategy
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