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

作者：Ramadori Giorgio; Konstantinidou Georgia; Venkateswaran Niranjan; Biscotti Tommasina; Morlock Lorraine; Galie Mirco; Williams Noelle S; Luchetti Michele; Santinelli Alfredo; Scaglioni Pier Paolo^*; Coppari Roberto

来源：Cell Metabolism, 2015, 21(1): 117-125.

DOI：10.1016/j.cmet.2014.11.020

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.

• 出版日期2015-1-6