An essential mechanism for the initiation of therapy- and castration-resistant PCa (t-CRPC), which is closely correlated with cancer stem cell (CSC) activity, has been identified as lineage plasticity in prostate cancer (PCa). For a study, researchers sought to investigate new targeted strategies and discover important driver(s) with mechanisms of action.
The in vitro prostasphere assay, the cell viability assay, and the in vivo stemness potential were all performed on several PCa cell lines that had undergone various genetic modifications. In order to assess clinical significance, bioinformatic techniques like Ingenuity pathway and Gene Set Enrichment Analysis were also performed. JAK or STAT1 inhibitors’ in vivo anti-tumor efficacy was investigated in the therapeutically applicable t-CRPC model.
They showed that the interferon-related signaling pathway plays an important role in increasing PCa stemness, which is connected with a large increase in the hallmark genes for interferon-related DNA damage resistance in metastatic PCa. The in vitro and in vivo CSC capabilities were suppressed by JAK-STAT1 signaling inhibition. IFIT5, a special JAK-STAT1 pathway downstream effector, works by speeding the turnover of certain microRNAs (such miR-128 and -101) that can target a number of CSC genes, to help PCa acquire stemness traits (such as BMI1, NANOG, and SOX2). The capacity of t-CRPC cells to initiate tumors in vivo and in vitro may both be dramatically reduced by knocking down IFIT5 in these cells.
The study demonstrated the crucial function of STAT1-IFIT5 in the development of PCSC and emphasized the clinical application of JAK or STAT1 inhibitors to stop the spread of t-CRPC.