title: Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis.
abstract: Targeted disruption of STAT3 function has proven to be a useful cancer therapeutic approach by inducing apoptotic cell death. Cucurbitacin is currently under development as a small molecule of STAT3 inhibitor to trigger cell death in many cancers. Here, we systematically studied the molecular mechanisms underlying cucurbitacin-induced cell death, in particular the involvement of autophagy. Treatment with cucurbitacin resulted in non-apoptotic cell death in a caspase-independent manner. Notably, cucurbitacin enhanced excessive conversion of lipidated LC3 (LC3-II) and accumulation of autophagosomes in many cell types. Such autophagy and cell death induced by cucurbitacin were independent of its ability to inhibit STAT3 function, but mainly mediated by enhanced production of mitochondrial-derived reactive oxygen species (ROS), and subsequently activation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK). Interestingly, both the autophagy inhibitor wortmannin and knockdown of Atg5 or Beclin 1 failed to rescue the cells from cucurbitacin-induced cell death, as suppression of autophagy induced the mode of cell death to shift from autophagic cell death to caspase-dependent apoptosis. Thus the present study provides new insights into the molecular mechanisms underlying cucurbitacin-mediated cell death and supports cucurbitacin as a potential anti-cancer drug through modulating the balance between autophagic and apoptotic modes of cell death.
authors.affiliation: Department of Pharmacology, Research Institute for Medical Science, Infection Signaling Network Research Center, Daejeon Regional Cancer Center, Daejeon, Republic of Korea.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Zhang
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Li
authors.forename: Kyeong Ah
authors.initials: KA
authors.lastname: Park
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Byun
authors.forename: Minho
authors.initials: M
authors.lastname: Won
authors.forename: Juhee
authors.initials: J
authors.lastname: Jeon
authors.forename: Yoonjung
authors.initials: Y
authors.lastname: Lee
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Seok
authors.forename: Seung-Won
authors.initials: SW
authors.lastname: Choi
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Jin
authors.initials: J
authors.lastname: Man Kim
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Chang Gue
authors.initials: CG
authors.lastname: Son
authors.forename: Zee-Won
authors.initials: ZW
authors.lastname: Lee
authors.forename: Han-Ming
authors.initials: HM
authors.lastname: Shen
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008954:Models, Biological; D010617:Phenanthridines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: C521281:5-(6'-triphenylphosphoniumhexyl)-5,6-dihydro-6-phenyl-3,8-phenanthridinediammine; D010617:Phenanthridines; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D014315:Triterpenes; C041246:cucurbitacin B; D008769:Methylnitronitrosoguanidine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; C038106:cucurbitacin I