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

Abstract

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.

The Bacteriostatic Protein Lipocalin 2 Is Induced in the Central Nervous System of Mice with West Nile Virus Encephalitis

“…(35) have important roles in host defense against WNV. These PRRs are known to mediate the activation of signal transduction pathways that include NF-B (36), and NF-B activation is known to induce Lcn2 gene expression (37)(38)(39) and occurs in WNV-infected cells (40). Murine astrocytes and microglia express the principal WNV-detecting RLRs (27,41) as well as TLRs, including TLR3 (41,42), which might contribute to Lcn2 gene expression via the activation of the NF-B pathway in these cells.…”

Neutrophil gelatinase- associated lipocalin as a screening test in prostate cancer

“…[13,16,17,[25][26][27][28] Although there are studies showing that increased serum NGAL levels indicate a relation with PCa diagnosis and poor prognosis, there is no study investigating possible role of NGAL in discrimination between benign, and malign diseases of the prostate. [29][30][31] In this study, potential role of NGAL in minimizing unnecessary biopsies as a biomarker was investigated and NGAL levels were found to be significant higher than PSA in PCa patients relative to BPH patients. ROC curve analysis is a good tool to manifest the characteristics of a biomarker.…”

Clinical significance of neutrophil gelatinase-associated lipocalin (NGAL) in colorectal cancer: a meta-analysis

“…In most of the common human cancers, NGAL expression is upregulated, for example in colorectal cancer, gastric cancer (Kubben et al, 2007), esophageal squamous cell carcinoma (Zhang et al, 2007), lung adenocarcinoma (Friedl et al, 1999), primary liver carcinoma (Li et al, 2012), breast cancer (Fernández et al, 2005), and thyroid neoplasia (Iannetti et al, 2008), while in a few conditions, NGAL expression is downregulated or remains debatable, for example in pancreatic cancer (Furutani et al, 1998;Laurell et al, 2006;Tong et al, 2008), prostate cancer (Mahadevan et al, 2011), and chronic myeloid leukemia (Villalva et al, 2008).…”