Various kinds of animal venoms and their components have been widely studied for potential therapeutic applications. This study\nevaluatedwhetherNemopilema nomurai jellyfish venom(NnV) has anticancer activity.NnVstrongly induced cytotoxicity ofHepG2\ncells through apoptotic cell death, as demonstrated by alterations of chromatic morphology, activation of procaspase-3, and an\nincrease in the Bax/Bcl-2 ratio. Furthermore, NnV inhibited the phosphorylation of PI3K, PDK1, Akt, mTOR, p70S6K, and 4EBP1,\nwhereas it enhanced the expression of p-PTEN. Interestingly, NnV also inactivated the negative feedback loops associated with\nAkt activation, as demonstrated by downregulation of Akt at Ser473 and mTOR at Ser2481. The anticancer effect of NnV was\nsignificant in a HepG2 xenograft mouse model, with no obvious toxicity. HepG2 cell death by NnV was inhibited by tetracycline,\nmetalloprotease inhibitor, suggesting that metalloprotease component in NnV is closely related to the anticancer effects. This study\ndemonstrates, for the first time, that NnV exerts highly selective cytotoxicity in HepG2 cells via dual inhibition of the Akt and\nmTOR signaling pathways, but not in normal cells.
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