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

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.

Position in bed is associated with left or right location in benign paroxysmal positional vertigo of the posterior semicircular canal.

PURPOSE: To determine if position during bedrest is related to the canal affected in posterior canal benign paroxysmal positional vertigo (BPPV). MATERIALS AND METHODS: Fifty-five individuals with posterior canal BPPV were investigated. Diagnosis was established if a consistent clinical history was found with vertigo and induced positional nystagmus elicited on the Dix-Hallpike test (DHT). Preference for left or right position during bed rest was determined before performing the DHT. All patients were treated by a single particle repositioning procedure, and relapses were investigated at the seventh and 30 days posttreatment. RESULTS: Forty-five individuals always slept on the same side (29 on the right, 16 on the left side), and 10 patients preferred to change sides during bed rest. Among those patients able to maintain a constant position during bed rest, 27 and 18 presented a positive DHT on the right and left sides, respectively. The canal affected was found to be significantly associated with side during bed rest (relative risk = 2.75; P = 0.01, Fisher exact test). DHT was negative in 86% of patients at 30 days. No differences were found between individuals who presented a constant position in bed and those who changed positions. CONCLUSIONS: Lateral supine position during bed rest is associated with the canal affected in BPPV. We speculate that gravity might facilitate the deposition of particulate material on the posterior semicircular near the ampulla canal during bed rest.