| Atg5 regulates phenethyl isothiocyanate-induced autophagic and apoptotic cell death in human prostate cancer cells. | |
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MedLine Citation:
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PMID: 19336571 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Ajay Bommareddy; Eun-Ryeong Hahm; Dong Xiao; Anna A Powolny; Alfred L Fisher; Yu Jiang; Shivendra V Singh |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-03-31 |
Journal Detail:
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Title: Cancer research Volume: 69 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-04-16 Completed Date: 2009-06-19 Revised Date: 2010-09-22 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3704-12 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Chemical Biology, and University of Pittsburgh Cancer Institute, Pennsylvania, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anticarcinogenic Agents / pharmacology* Apoptosis / drug effects* Autophagy / drug effects* Caenorhabditis elegans / drug effects Cell Line, Tumor Humans Isothiocyanates / pharmacology* Male Mice Mice, Nude Microtubule-Associated Proteins / metabolism* Monomeric GTP-Binding Proteins / biosynthesis Neuropeptides / biosynthesis Oncogene Protein v-akt / metabolism Phosphorylation Prostatic Neoplasms / drug therapy*, metabolism, pathology Protein Kinases / metabolism Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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CA101753/CA/NCI NIH HHS; CA115498/CA/NCI NIH HHS; K08 AG028977/AG/NIA NIH HHS; R01 CA101753-06/CA/NCI NIH HHS; R01 CA115498-04/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ATG5 protein, human; 0/Anticarcinogenic Agents; 0/Isothiocyanates; 0/Microtubule-Associated Proteins; 0/Neuropeptides; 0/RHEB protein, human; 0/Rheb protein, mouse; 2257-09-2/phenethyl isothiocyanate; EC 2.7.-/Protein Kinases; EC 2.7.1.-/mTOR protein; EC 2.7.11.1/Oncogene Protein v-akt; EC 3.6.5.2/Monomeric GTP-Binding Proteins |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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