title: Cyclophilin D modulates cell death transition from early apoptosis to programmed necrosis induced by honokiol.
abstract: Honokiol is a pharmacologically active small molecule with multifunctional antitumor effects. Although plenty of literature is available on honokiol-triggered apoptosis and programmed necrosis, few studies have investigated the potential existence of death mode transition from apoptosis to programmed necrosis. In the current study, we demonstrated that the necrotic cell population (PI-positive) gradually increased and the early-stage apoptotic cell population (PI-negative and AV-positive) decreased in a dose- and time-dependent manner following honokiol treatment. Furthermore, we demonstrated that these PI-positive cells were under necrotic cell death, since no late-apoptosis characteristics including conspicuous chromatin condensation or DNA ladder patterns were detected. These results demonstrated that cells suffered death mode transition from early-stage apoptosis to programmed necrosis with the increase of honokiol dose or treatment time. The protein expression of RIP3 markedly increased in parallel with HNK-triggered death mode transition, while the expression of RIP1 decreased. Cyclophilin D expression increased during cell death mode transition, and inhibition of cyclophilin D by cyclosporin A clearly blocked HNK-triggered programmed necrosis. These data indicated that honokiol-induced programmed necrosis and death mode transition are potentially RIP3‑dependent, cyclophilin D-regulated. Further results showed that blocked cyclophilin D by cyclosporin A inhibited HNK-induced necrosis, but did not affect HNK-induced RIP3 overexpression. This indicated that cyclophilin D was a potential modulator at downstream of RIP3. In conclusion, honokiol triggers a potential RIP3-dependent cell death mode transition from early-stage apoptosis to programmed necrosis, which is highly regulated by cyclophilin D.
authors.affiliation: Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tian
authors.forename: Dong
authors.initials: D
authors.lastname: Xu
authors.forename: Weidong
authors.initials: W
authors.lastname: Han
authors.forename: Haifei
authors.initials: H
authors.lastname: He
authors.forename: Hongke
authors.initials: H
authors.lastname: Cai
authors.forename: Hailong
authors.initials: H
authors.lastname: Chen
authors.forename: Meiqi
authors.initials: M
authors.lastname: Zhou
authors.forename: Jiani
authors.initials: J
authors.lastname: Chen
authors.forename: Yong-Chuan
authors.initials: YC
authors.lastname: Deng
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000494:pharmacology*; D006801:Humans; D017705:Lignans / Q000008:administration & dosage*; D009336:Necrosis / Q000235:genetics*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins; D017705:Lignans; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C119705:RIPK3 protein, human