title: Diet-induced unresolved ER stress hinders KRAS-driven lung tumorigenesis.
abstract: 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.
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ramadori
authors.affiliation: Department of Internal Medicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Konstantinidou
authors.affiliation: Department of Internal Medicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Venkateswaran
authors.affiliation: Section of Pathological Anatomy, Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60020 Ancona, Italy.
authors.forename: Tommasina
authors.initials: T
authors.lastname: Biscotti
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Morlock
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Mirco
authors.initials: M
authors.lastname: Galié
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, 60020 Ancona, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Luchetti
authors.affiliation: Section of Pathological Anatomy, Department of Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60020 Ancona, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Santinelli
authors.affiliation: Department of Internal Medicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: pier.scaglioni@utsouthwestern.edu.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva 4, Switzerland. Electronic address: roberto.coppari@unige.ch.
authors.forename: Roberto
authors.initials: R
authors.lastname: Coppari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004032:Diet; D015536:Down-Regulation; D004318:Doxycycline / Q000633:toxicity; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D010654:Phenylbutyrates / Q000633:toxicity*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D056811:Unfolded Protein Response / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D010654:Phenylbutyrates; D034741:RNA, Small Interfering; C075773:4-phenylbutyric acid; D018631:ras Proteins; D022021:Tacrolimus Binding Proteins; C491675:Fkbp10 protein, mouse; D004318:Doxycycline