Kavain ablates the radio-resistance of IDH-wildtype glioblastoma by targeting LITAF/NF-κB pathway.

Abstract

Glioblastoma multiforma (GBM) is the most malignant intrinsic tumor of the central nervous system(CNS), with high morbidity of 3.19/100,000 per year and a poor 5-year survival rate (< 5%) worldwide. Numerousstudies have indicated that GBM shows remarkable radioresistance and aggressive recurrence. However, themechanisms to endow GBM cells with radioresistance are complex and unclear. Cell growth curve and colony formation assays were used to analyze the radioresistance of GBM.Immunoprecipitation and immunoblotting experiments were carried out to analyze protein expression andinteraction. In the present study, we found that LITAF, lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-αfactor, is up-regulated both in mRNA and protein in GBM tumors. Meanwhile, we observed that high LITAFexpression contributes to radioresistance of GBM cell lines (including U87, U251, DK, and AM38 cells), indicated byknockout or knockdown of LITAF in cells sensitizing them to radiation treatment both in vitro and in vivo.Furthermore, we demonstrated that kavain, an active constituent of Piper methysticum Forst., effectively ablatesGSC-like cells' (such as CD133 + U87, U251, DK, and AM38 populations) radioresistance in a LITAF-dependentmanner. In mechanism, our results indicated that 1) the elevation of LITAF in GBM cells activates the NF-κBpathway to promote mesenchymal transition, and 2) kavain disturbs STAT6B/LITAF protein interaction and thenexpels LITAF from the nucleus. Therefore, we consider that kavain may be a potential candidate to develop anirradiation therapy adjuvant for GBM.