mTOR signaling pathway is inhibited downstream of the cyclophilin D-mediated mitochondrial permeability transition in honokiol-triggered regulated necrosis

摘要: Honokiol (HNK) is a pharmacologically active small molecule that isolated from the traditional Chinese medicinal herb, houpu. It may induce diversified types of regulated cell death, which are dependent on different and varying concentrations therapeutic agent. We previously reported HNK triggers cyclophilin D (CypD)-mediated necrosis in various lines at certain (two‑fold higher than its half maximal inhibitory concentration). Subsequent study revealed induced death transition early apoptosis to parallel with increase dose. In current study, lower concentration (30 µg/ml) also simplex CypD‑mediated mitochondrial permeability (MPT)‑associated HEK‑293 human embryonic kidney line. HNK, 30 µg/ml, necrotic cells, was demonstrated by positive staining for propidium iodide. No DNA ladder patterns or apoptotic bodies were detected cells underwent this type death. Caspase‑8 ‑3 not activated during process HNK‑induced necrosis. addition, pan‑caspase inhibitor, z‑VAD‑fmk receptor‑interacting protein 1 necrostatin‑1 did inhibit However, CypD cyclosporin A (CsA), blocked These findings indicate µg/ml CypD-mediated MPT‑associated cells. Furthermore, HNK-triggered mammalian target rapamycin (mTOR) signaling pathway inhibited. Pretreatment CsA, therefore, inhibits HNK‑triggered reverses dephosphorylation Akt, eIF4E‑binding S6 kinase. This indicated mTOR effective downstream MPT before onset plasma membrane breakdown process. Therefore, it has been first time, best our knowledge, inhibited HNK-induced