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Diet-induced unresolved ER stress hinders KRAS-driven lung tumorigenesis.

  • Ramadori G Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva 4, Switzerland.
  • Konstantinidou G Department of Internal Medicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Venkateswaran N Department of Internal Medicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Biscotti T Section of Pathological Anatomy, Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60020 Ancona, Italy.
  • Morlock L Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Galié M Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva 4, Switzerland.
  • Williams NS Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Luchetti M Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, 60020 Ancona, Italy.
  • Santinelli A Section of Pathological Anatomy, Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60020 Ancona, Italy.
  • Scaglioni PP Department of Internal Medicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: pier.scaglioni@utsouthwestern.edu.
  • Coppari R Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva 4, Switzerland. Electronic address: roberto.coppari@unige.ch.
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  • 2014-12-24
Published in:
  • Cell metabolism. - 2015
Animals
Cell Line, Tumor
Cell Transformation, Neoplastic
Diet
Down-Regulation
Doxycycline
Endoplasmic Reticulum Stress
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
Male
Mice
Mice, SCID
Molecular Chaperones
Phenylbutyrates
RNA Interference
RNA, Small Interfering
Tacrolimus Binding Proteins
Transplantation, Heterologous
Unfolded Protein Response
ras Proteins
English Dietary effects on tumor biology can be exploited to unravel cancer vulnerabilities. Here, we present surprising evidence for anti-proliferative action of high-calorie-diet (HCD) feeding on KRAS-driven lung tumors. Tumors of mice that commenced HCD feeding before tumor onset displayed defective unfolded protein response (UPR) and unresolved endoplasmic reticulum (ER) stress. Unresolved ER stress and reduced proliferation are reversed by chemical chaperone treatment. Whole-genome transcriptional analyses revealed FKBP10 as one of the most downregulated chaperones in tumors of the HCD-pre-tumor-onset group. FKBP10 downregulation dampens tumor growth in vitro and in vivo. Providing translational value to these results, we report that FKBP10 is expressed in human KRAS-positive and -negative lung cancers, but not in healthy parenchyma. Collectively, our data shed light on an unexpected anti-tumor action of HCD imposed before tumor onset and identify FKBP10 as a putative therapeutic target to selectively hinder lung cancer.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/245321
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