Document Detail


Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs.
MedLine Citation:
PMID:  23460482     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress-induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon.
Authors:
Marine Gilabert; Maria Inés Vaccaro; Martin E Fernandez-Zapico; Ezequiel L Calvo; Olivier Turrini; Véronique Secq; Stéphane Garcia; Vincent Moutardier; Gwen Lomberk; Nelson Dusetti; Raul Urrutia; Juan L Iovanna
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cellular physiology     Volume:  228     ISSN:  1097-4652     ISO Abbreviation:  J. Cell. Physiol.     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-05-28     Completed Date:  2013-09-03     Revised Date:  2014-06-09    
Medline Journal Info:
Nlm Unique ID:  0050222     Medline TA:  J Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1834-43     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Wiley Periodicals, Inc.
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MeSH Terms
Descriptor/Qualifier:
Animals
Autophagy / drug effects,  genetics
Biomarkers, Pharmacological / metabolism
Cell Line, Tumor
Deoxycytidine / administration & dosage,  analogs & derivatives*
Drug Resistance, Neoplasm / genetics
Endoplasmic Reticulum Stress / drug effects,  genetics
Gene Expression Regulation, Neoplastic
Humans
Membrane Proteins / antagonists & inhibitors,  genetics*,  metabolism
Mice
Pancreatic Neoplasms / drug therapy*,  genetics*,  pathology
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
DK52913/DK/NIDDK NIH HHS; P30DK084567/DK/NIDDK NIH HHS; P50 CA102701/CA/NCI NIH HHS; P50 CA102701/CA/NCI NIH HHS; R01 DK052913/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Biomarkers, Pharmacological; 0/Membrane Proteins; 0/VMP1 protein, human; 0W860991D6/Deoxycytidine; B76N6SBZ8R/gemcitabine

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