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Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
- Source :
- CONICET Digital (CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, instacron:CONICET
- Publication Year :
- 2013
- Publisher :
- Wiley, 2013.
-
Abstract
- 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. Fil: Gilabert, Mariana. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia Fil: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Fernandez Zapico, Martín E.. Mayo Clinic Cancer Center; Estados Unidos Fil: Calvo, Ezequiel L.. Molecular Endocrinology and Oncology Research Center; Canadá Fil: Turrini, Olivier. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia Fil: Secq, Véronique. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia Fil: Garcia, Stéphanie. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia Fil: Moutardier, Vincent. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia Fil: Lomberk, Gwen. Mayo Clinic; Estados Unidos Fil: Dusetti, Nelson. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia Fil: Urrutia, Raul. Mayo Clinic; Estados Unidos Fil: Iovanna, Juan L.. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Francia
- Subjects :
- CIENCIAS MÉDICAS Y DE LA SALUD
Physiology
Clinical Biochemistry
Biology
Deoxycytidine
Article
Biomarkers, Pharmacological
Neoplasm genetics
Mice
Pancreatic tumor
Cell Line, Tumor
Pancreatic cancer
Autophagy
medicine
Animals
Humans
VMP1
Extramural
Membrane Proteins
purl.org/becyt/ford/3.1 [https]
Cell Biology
Bioquímica y Biología Molecular
Endoplasmic Reticulum Stress
medicine.disease
Xenograft Model Antitumor Assays
Gemcitabine
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms
Medicina Básica
Drug Resistance, Neoplasm
Immunology
Cancer research
purl.org/becyt/ford/3 [https]
Cell response
Chemotherapeutic drugs
Subjects
Details
- ISSN :
- 00219541
- Volume :
- 228
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular Physiology
- Accession number :
- edsair.doi.dedup.....a69d3da5bf1f395adcc3544f6bcbe01f