TY - JOUR
T1 - Diet-induced unresolved ER stress hinders KRAS-driven lung tumorigenesis
AU - Ramadori, Giorgio
AU - Konstantinidou, Georgia
AU - Venkateswaran, Niranjan
AU - Biscotti, Tommasina
AU - Morlock, Lorraine
AU - Galié, Mirco
AU - Williams, Noelle S.
AU - Luchetti, Michele
AU - Santinelli, Alfredo
AU - Scaglioni, Pier Paolo
AU - Coppari, Roberto
N1 - Funding Information:
We thank Ariane Widmer, Anne Charollais, Carolyn Heckenmeyer, and Laurent Vinet for technical support; Drs. Claes Wollheim and Pedro Herrera (UNIGE) for critical reading of the manuscript; and Dr. James Richardson (UTSW) for pathological examination of the lungs. This work was supported by CPRIT RP101496 (G.K.), ACS Award 13-068-01-TBG and Lung Cancer SPORE P50CA70907 (P.P.S.), by European Commission (Marie Curie CIG 320898 and ERC-Consolidator 614847), and by Swiss National Science Foundation (310030_146533/1) (R.C.). This work has also received the unrestricted support of the Louis-Jeantet Foundation (R.C.).
PY - 2015/1/6
Y1 - 2015/1/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2014.11.020
DO - 10.1016/j.cmet.2014.11.020
M3 - Article
C2 - 25533479
AN - SCOPUS:84920656075
VL - 21
SP - 117
EP - 125
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 1
ER -