ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner

BMC Cancer

Research Article

Jeffrey Rodvold¹  Maurizio Zanetti¹  Navin R Mahadevan¹  Antonio Fernández Pérez¹  Gonzalo Almanza¹  Matthew C Wheeler¹ 

[1] The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, 92093-0815, La Jolla, CA, USA;

关键词: Endoplasmic Reticulum Stress;    Prostate Cancer Cell;    Unfold Protein Response;    Enhanced Green Fluorescent Protein;    Human Prostate Cancer Cell;   

DOI  :  10.1186/1471-2407-11-229

 received in 2010-11-30, accepted in 2011-06-07,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundTumor cells adapt to endoplasmic reticulum (ER) stress through a set of conserved intracellular pathways, as part of a process termed the unfolded protein response (UPR). The expression of UPR genes/proteins correlates with increasing progression and poor clinical outcome of several tumor types, including prostate cancer. UPR signaling can activate NF-κB, a master regulator of transcription of pro-inflammatory, tumorigenic cytokines. Previous studies have shown that Lipocalin 2 (Lcn2) is upregulated in several epithelial cancers, including prostate cancer, and recently Lcn2 was implicated as a key mediator of breast cancer progression. Here, we hypothesize that the tumor cell UPR regulates Lcn2 production.MethodsWe interrogated Lcn2 regulation in murine and human prostate cancer cells undergoing pharmacological and physiological ER stress, and tested UPR and NF-κB dependence by using pharmacological inhibitors of these signaling pathways.ResultsInduction of ER stress using thapsigargin (Tg), a canonical pharmacologic ER stress inducer, or via glucose deprivation, a physiologic ER stressor present in the tumor microenvironment, upregulates LCN2 production in murine and human prostate cancer cells. Inhibition of the UPR using 4-phenylbutyric acid (PBA) dramatically decreases Lcn2 transcription and translation. Inhibition of NF-κB in prostate cancer cells undergoing Tg-mediated ER stress by BAY 11-7082 abrogates Lcn2 upregulation.ConclusionsWe conclude that the UPR activates Lcn2 production in prostate cancer cells in an NF-κB-dependent manner. Our results imply that the observed upregulation of Lipocalin 2 in various types of cancer cells may be the direct consequence of concomitant UPR activation, and that the ER stress/Lipocalin 2 axis is a potential new target for intervention in cancer progression.

【 授权许可】

Unknown   
© Mahadevan et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.