Alternatively spliced isoforms of IL-32 differentially influence cell death pathways in cancer cell lines

This study demonstrates that IL-32 and IL-32β can induce caspase-8-dependent cell death whereas this was not observed for IL-32α. Overexpression of IL-32β or IL-32 but not IL-32α, resulted in enhanced expression of the survival cytokine IL-8. Furthermore, restoring the IL-8 signaling pathway by overexpressing CXCR1 in HEK293 cells, rescued IL-32β but not IL-32-induced cell death. Interestingly, IL-32 was able to downregulate CXCR1 and thereby induce cell death. Subsequent studies into the role of IL-32 in thyroid cancer (TC) revealed that several IL-32 isoforms, IL-8, and CXCR1 are expressed in TC cell lines and specimens. Remarkably, TC cell lines were found to produce high concentrations of IL-8, indicating an important role for IL-8 in the survival-signaling pathway in these cells. Intriguingly, a significant correlation between the IL-8 receptor CXCR1 and IL-32 was observed in TC specimens, while this was not observed for the other IL-32 splice variants. Blocking IL-32 alternative splicing by Isoginkgetin resulted in predominant expression of IL-32 splice variants and cell death in TC cell lines. All together, modulation of IL-32 alternative splicing could represent a novel strategy for the treatment of malignancies, in particular thyroid cancer.
Source: Carcinogenesis - Category: Cancer & Oncology Authors: Tags: Original Manuscript Source Type: research