Document Detail


The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells.
MedLine Citation:
PMID:  25296977     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer.
Authors:
Lymor Ringer; Paul Sirajuddin; Lucas Tricoli; Sarah Waye; Muhammad Umer Choudhry; Erika Parasido; Angiela Sivakumar; Mary Heckler; Aisha Naeem; Iman Abdelgawad; Xuefeng Liu; Adam S Feldman; Richard J Lee; Chin-Lee Wu; Venkata Yenugonda; Bhaskar Kallakury; Anatoly Dritschilo; John Lynch; Richard Schlegel; Olga Rodriguez; Richard G Pestell; Maria Laura Avantaggiati; Chris Albanese
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Oncotarget     Volume:  5     ISSN:  1949-2553     ISO Abbreviation:  Oncotarget     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-29     Completed Date:  -     Revised Date:  2014-12-03    
Medline Journal Info:
Nlm Unique ID:  101532965     Medline TA:  Oncotarget     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10678-91     Citation Subset:  IM    
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Descriptor/Qualifier:
Grant Support
ID/Acronym/Agency:
P30 CA051008/CA/NCI NIH HHS; T32 CA009686/CA/NCI NIH HHS; UL1 TR000101/TR/NCATS NIH HHS

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