Lipocalin-2 receptor (LCN2R) also known as solute carrier family 22 member 17 (SLC22A17), plays an unexplored role that potentially induces cancer death or survival depending on iron status. The specific role of LCN2R in prostate cancer cells has not yet been elucidated, although LCN2 is known to be associated with inflammation and tumor growth in prostate cancer. This study aims to clarify the function of LCN2R in the human prostate.

Data acquisition, pre-processing, and analysis. We use GEPIA 2 (http://gepia2.cancer-pku.cn/#general) and cBioPortal (https://www.cbioportal.org/) to obtain mRNA expression profiles and related clinical information on LCN2R in various cancers from the TCGA cohorts. We compared the expressions of LCN2R in 31 types of tumor tissues and their matching normal tissues in GEPIA 2. We also explore the associations between LCN2R expression and clinicopathological characteristics or progression-free survival rates using cBioPortal. For prostate adenocarcinoma (PRAD), we divided patients into a high–expression group and a low-expression group based on mean expression levels. We use the Kaplan-Meier method to compare progression-free survival, the time from cancer diagnosis to the last follow-up of each patient. We also examined the correlation of LCN2R RNA between expression levels and clinicopathological characteristics such as age, pathologic stage, and the Gleason score of 389 prostate cancer tissues of newly diagnosed prostate cancer patients using a chi-square test.

Our results from cell-based assays and xenograft studies demonstrate that LCN2R suppresses prostate cancer cell growth in vitro and in vivo. Further bioinformatics analysis suggested that it acts as a tumor suppressor gene in the human prostate, and low expression of LCN2R is associated with unfavorable clinicopathological factors and survival outcomes for prostate cancer. We found that p53 induces the expression of LCN2R, while the androgen agonist R1881 represses it. Interestingly, neither ferric ammonium citrate (FAC) nor iron chelator (Dp44mT) affected the expression of LCN2R. However, LCN2R was found to regulate iron influx and increase sensitivity to RSL3-induced ferroptosis in prostate cancer cells. Furthermore, LCN2R negatively modulates the effect of FAC on ferritin heavy chain 1 expression, an intracellular iron storage protein, while improving cisplatin-induced apoptosis or Dp44mT-induced apoptosis in prostate cancer cells.

Our findings reveal that LCN2R, a gene regulated by p53 and androgen, acts as an iron transporter that promotes ferroptosis and modulates the sensitivity of prostate cancer cells to cisplatin-induced and Dp44mT-induced apoptosis. Therefore, targeting LCN2R may provide a novel therapeutic strategy for prostate cancer.