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.
Highlights
Tumor 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)
We demonstrate that the ER stress response in murine and human prostate cancer cells drives the production of Lipocalin 2 (Lcn2) in an NF-B-dependent manner, and that diminishing the UPR dramatically decreases Lcn2 transcription and translation
We first suspected a link between Lcn2 and tumor cell ER stress when we found that among the genes most upregulated in murine A20 lymphoma cells following treatment with thapsigargin (Tg), a canonical inducer of ER stress, was Lcn2 [19] (Additional File 1 Table S1)
Summary
Tumor 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. Previous studies have shown that Lipocalin 2 (Lcn2) is upregulated in several epithelial cancers, including prostate cancer, and recently Lcn was implicated as a key mediator of breast cancer progression. We hypothesize that the tumor cell UPR regulates Lcn production. Lipocalin 2 (Lcn2), otherwise known as neutrophil gelatinase-associated lipocalin (NGAL), is upregulated in several solid cancers, and has been shown to facilitate tumor progression. Yang et al [1] linked the elevated LCN2 levels found in breast cancer with increased tumor progression and metastasis and revealed its direct role in facilitating the epithelial-to-mesenchymal transition (EMT) in breast cancer cells. The regulation and function of Lcn in epithelial cancers remain unknown. NF-B, a master regulator of inflammation, drives Lcn transcription in malignant and untransformed cells [2,10,11]
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