Diet-Induced Unresolved ER Stress Hinders KRAS-Driven Lung Tumorigenesis

被引：47

作者：

Ramadori, Giorgio ^{[1
]}

Konstantinidou, Georgia ^{[2
]}

Venkateswaran, Niranjan ^{[2
]}

Biscotti, Tommasina ^{[3
]}

Morlock, Lorraine ^{[4
]}

Galie, Mirco ^{[1
]}

Williams, Noelle S. ^{[4
]}

Luchetti, Michele ^{[5
]}

Santinelli, Alfredo ^{[3
]}

Scaglioni, Pier Paolo ^{[2
]}

Coppari, Roberto ^{[1
]}

机构：

[1] Univ Geneva, Dept Cell Physiol & Metab, CH-1211 Geneva 4, Switzerland

[2] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Simmons Canc Ctr, Dallas, TX 75390 USA

[3] Univ Politecn Marche, Sect Pathol Anat, Dept Biomed Sci & Publ Hlth, I-60020 Ancona, Italy

[4] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

[5] Univ Politecn Marche, Clin Med, Dipartimento Sci Clin & Mol, I-60020 Ancona, Italy

来源：

CELL METABOLISM | 2015年 / 21卷 / 01期

基金：

瑞士国家科学基金会;

关键词：

UNFOLDED-PROTEIN-RESPONSE; GLUCOSE-HOMEOSTASIS; REGULATORY SUBUNITS; CANCER; OBESITY; PI3K; ACTIVATION; RAS; ADENOCARCINOMAS; MECHANISMS;

D O I：

10.1016/j.cmet.2014.11.020

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：117 / 125

页数：9

共 35 条

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