Anticancer Effect of Nemopilema nomurai Jellyfish Venom on HepG2 Cells and a Tumor Xenograft Animal Model

Abstract

Various kinds of animal venoms and their components have been widely studied for potential therapeutic applications. This study evaluated whether Nemopilema nomurai jellyfish venom (NnV) has anticancer activity. NnV strongly induced cytotoxicity of HepG2 cells through apoptotic cell death, as demonstrated by alterations of chromatic morphology, activation of procaspase-3, and an increase in the Bax/Bcl-2 ratio. Furthermore, NnV inhibited the phosphorylation of PI3K, PDK1, Akt, mTOR, p70S6K, and 4EBP1, whereas it enhanced the expression of p-PTEN. Interestingly, NnV also inactivated the negative feedback loops associated with Akt activation, as demonstrated by downregulation of Akt at Ser473 and mTOR at Ser2481. The anticancer effect of NnV was significant in a HepG2 xenograft mouse model, with no obvious toxicity. HepG2 cell death by NnV was inhibited by tetracycline, metalloprotease inhibitor, suggesting that metalloprotease component in NnV is closely related to the anticancer effects. This study demonstrates, for the first time, that NnV exerts highly selective cytotoxicity in HepG2 cells via dual inhibition of the Akt and mTOR signaling pathways, but not in normal cells.

Nemopilema nomurai jellyfish venom exerts an anti-metastatic effect by inhibiting Smad- and NF-κB-mediated epithelial–mesenchymal transition in HepG2 cells

“…Our previous study for the first time showed that NnV suppresses hepatic tumour growth both in vitr o and in viv o 31 . Especially, tumour tissues in NnV-treated animals were less diffuse (more compact) and showed stronger E-cadherin expression than non-treated animals.…”

“…Jellyfish venom is composed of various molecules including peptides, enzymes, neurotoxin, cytolysin, haemolysin with biological effects 38 – 46 . According to our previous study on the anti-cancer effect of NnV, metalloprotease component in NnV might be the main component contributing to apoptotic HepG2 cell death 31 . In support of this notion, other venoms (of snakes and spiders) also have metalloprotease activities that inhibit cell adhesion, proliferation, migration, invasion, and angiogenesis 47 – 50 .…”

“…Our previous study showed that N. nomurai venom (NnV) induces apoptotic cell death via dual inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) pathways in HepG2 human hepatocellular carcinoma cells and in a nude mouse model 31 . We also observed that tumour tissue in the NnV-treated group was more compact than that in the non-treated control group.…”

Biotechnological Applications of Scyphomedusae

“…Crude venom from Nemopilema nomurai had cytotoxic and cytolytic effects on heart and muscle myoblasts in mice and blood cells from different organisms, including humans [112]. More recently, an anti-tumoral activity was assessed in a model animal for extracts of crude venom from the same species [158]. Cyanea nozakii crude venom was toxic for colon cancer and hepatoma cells in humans [159].…”

Proteomic Investigation to Identify Anticancer Targets of Nemopilema nomurai Jellyfish Venom in Human Hepatocarcinoma HepG2 Cells

“…Jellyfish glycoprotein qniumucin can prevent articular cartilage degeneration in in vivo studies using an osteoarthritis (OA) model [ 27 ]. Our most recent report demonstrated that NnV exerts highly selective cytotoxicity in HepG2 cells via dual inhibition of the Akt and mTOR signaling pathways, but normal cells remained unaffected [ 28 ]. In the present work, we have analyzed the potential therapeutic targets of NnV at the proteomic level for the first time.…”