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Cucurbitacin induces autophagy through mitochondrial ROS production which counteracts to limit caspase-dependent apoptosis.
MedLine Citation:
PMID:  22441021     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Targeted disruption of STAT3 function has been proved 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:
Tiejun Zhang; Yuwen Li; Kyeong Ah Park; Hee Sun Byun; Minho Won; Juhee Jeon; Yoonjung Lee; Jeong Ho Seok; Seung-Won Choi; Sang-Hee Lee; Jin Man Kim; Ji Hoon Lee; Chang Gue Son; Zee-Won Lee; Gang Min Hur
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-01
Journal Detail:
Title:  Autophagy     Volume:  8     ISSN:  1554-8635     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-3-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101265188     Medline TA:  Autophagy     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Pharmacology; Research Institute for Medical Science; Infection Signaling Network Research Center; Daejeon Regional Cancer Center; Daejeon, Republic of Korea; Department of Neurosurgery; Research Institute for Medical Science; Infection Signaling Network Research Center; Daejeon Regional Cancer Center; Daejeon, Republic of Korea.
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