title: ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Induction 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: The Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0815, USA.
authors.forename: Navin R
authors.initials: NR
authors.lastname: Mahadevan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rodvold
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Almanza
authors.forename: Antonio Fernández
authors.initials: AF
authors.lastname: Pérez
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Wheeler
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zanetti
mesh_terms: D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009570:Nitriles / Q000494:pharmacology; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D010654:Phenylbutyrates / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D013450:Sulfones / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009570:Nitriles; D015513:Oncogene Proteins; D010654:Phenylbutyrates; D011518:Proto-Oncogene Proteins; D013450:Sulfones; D014415:Tunicamycin; C071332:Lcn2 protein, mouse; D019284:Thapsigargin; C075773:4-phenylbutyric acid; D005947:Glucose