Dipeptidyl peptidase‐8 induces sorafenib resistance via binding with c‐Rel to mediate NF‐κB signaling in hepatocellular carcinoma

Abstract Sorafenib is the important first‐standard drug for patients with advanced hepatocellular carcinoma (HCC). A major obstacle to successful treatment is sorafenib resistance. However, the mechanism of sorafenib resistance is unclear. The present study aimed to determine the involvement of dipeptidyl peptidase‐8 (DPP8) in sorafenib resistance. DPP8 expression was detected using quantitative real‐time PCR (qPCR) and western blot analysis. The effect of DPP8 on sorafenib resistance was examined using terminal deoxynulceotidyl transferase nick‐end‐labeling (TUNEL), colony formation, flow cytometry, luciferase reporter, immunofluorescence, and immunoprecipitation (IP) assays. We found that DPP8 mRNA and protein levels were dramatically upregulated in HCC. Gene set enrichment analysis (GSEA) illustrated that DPP8 might be involved in apoptosis regulation. Downregulation of DPP8 substantially promoted the sensitivity of HCC cells to sorafenib. Further analysis showed that DPP8 might regulate nuclear factor kappa B (NF‐κB) signaling, which was confirmed using a luciferase reporter assay. Downregulation of DPP8 decreased the expression levels of downstream genes of the NF‐κB pathway. IP showed that DPP8 can interact with NF‐κB subunit c‐Rel, an important protein of NF‐κB signaling. Finally, a drug combination of sorafenib and Val‐boroPro induced higher mortality of HCC cells than sorafenib alone in DPP8‐upregulated cells. Our findings indicated that using the inhibitor Val‐boroPro might be a promising method to enhance sorafenib sensitivity in advanced HCC.