Document Detail

Atg5 regulates phenethyl isothiocyanate-induced autophagic and apoptotic cell death in human prostate cancer cells.
MedLine Citation:
PMID:  19336571     Owner:  NLM     Status:  MEDLINE    
Phenethyl isothiocyanate (PEITC) is a promising cancer chemopreventive agent but the mechanism of its anticancer effect is not fully understood. We now show, for the first time, that PEITC treatment triggers Atg5-dependent autophagic and apoptotic cell death in human prostate cancer cells. Exposure of PC-3 (androgen independent, p53 null) and LNCaP (androgen responsive, wild-type p53) human prostate cancer cells to PEITC resulted in several specific features characteristic of autophagy, including appearance of membranous vacuoles, formation of acidic vesicular organelles, and cleavage and recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes. A normal human prostate epithelial cell line (PrEC) was markedly more resistant toward PEITC-mediated cleavage and recruitment of LC3 compared with prostate cancer cells. Although PEITC treatment suppressed activating phosphorylations of Akt and mammalian target of rapamycin (mTOR), which are implicated in regulation of autophagy by different stimuli, processing and recruitment of LC3 was only partially/marginally reversed by ectopic expression of constitutively active Akt or overexpression of mTOR-positive regulator Rheb. The PEITC-mediated apoptotic DNA fragmentation was significantly attenuated in the presence of a pharmacologic inhibitor of autophagy (3-methyl adenine). Transient transfection of LNCaP and PC-3 cells with Atg5-specific small interfering RNA conferred significant protection against PEITC-mediated autophagy as well as apoptotic DNA fragmentation. A xenograft model using PC-3 cells and Caenorhabditis elegans expressing a lgg-1:GFP fusion protein provided evidence for occurrence of PEITC-induced autophagy in vivo. In conclusion, the present study indicates that Atg5 plays an important role in regulation of PEITC-induced autophagic and apoptotic cell death.
Ajay Bommareddy; Eun-Ryeong Hahm; Dong Xiao; Anna A Powolny; Alfred L Fisher; Yu Jiang; Shivendra V Singh
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-03-31
Journal Detail:
Title:  Cancer research     Volume:  69     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-04-16     Completed Date:  2009-06-19     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3704-12     Citation Subset:  IM    
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MeSH Terms
Anticarcinogenic Agents / pharmacology*
Apoptosis / drug effects*
Autophagy / drug effects*
Caenorhabditis elegans / drug effects
Cell Line, Tumor
Isothiocyanates / pharmacology*
Mice, Nude
Microtubule-Associated Proteins / metabolism*
Monomeric GTP-Binding Proteins / biosynthesis
Neuropeptides / biosynthesis
Oncogene Protein v-akt / metabolism
Prostatic Neoplasms / drug therapy*,  metabolism,  pathology
Protein Kinases / metabolism
TOR Serine-Threonine Kinases
Xenograft Model Antitumor Assays
Grant Support
CA101753/CA/NCI NIH HHS; CA115498/CA/NCI NIH HHS; K08 AG028977/AG/NIA NIH HHS; K08 AG028977/AG/NIA NIH HHS; R01 CA101753/CA/NCI NIH HHS; R01 CA101753-06/CA/NCI NIH HHS; R01 CA115498/CA/NCI NIH HHS; R01 CA115498-04/CA/NCI NIH HHS; R21 AG029870/AG/NIA NIH HHS
Reg. No./Substance:
0/ATG5 protein, human; 0/Anticarcinogenic Agents; 0/Isothiocyanates; 0/Microtubule-Associated Proteins; 0/Neuropeptides; 0/RHEB protein, human; 0/Rheb protein, mouse; 6U7TFK75KV/phenethyl isothiocyanate; EC 2.7.-/Protein Kinases; EC protein, human; EC Serine-Threonine Kinases; EC protein, mouse; EC Protein v-akt; EC GTP-Binding Proteins

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