PI3Kδ Is a Therapeutic Target in Hepatocellular Carcinoma

Abstract

Class I phosphoinositide 3-kinase (PI3K) signaling is a major pathway in human cancer development and progression. Among the four PI3K isoforms, PI3K alpha and PI3K beta are ubiquitously expressed, whereas PI3K. and PI3K delta are found primarily in leukocytes. Until now, PI3K targeting in solid tumors has focused on inhibiting PI3K alpha-mediated and PI3K beta-mediated cancer cell-intrinsic PI3K activity. The role of PI3K delta in solid tumors is unknown. Here, we evaluated the effects of PI3K delta using established hepatocellular carcinoma (HCC) cells, malignant hepatocytes derived from patients with advanced HCC, murine models, and HCC tissues using RNA sequencing, quantitative PCR, immunoblotting, immunofluorescence, microarray, liquid chromatography-tandem mass spectrometry, and kinase assay. We established a chemical carcinogenesis model of liver malignancy that reflects the malignant phenotype and the in vivo environment of advanced HCC. In this in vivo advanced HCC-mimic system using HCC cells treated with hydrogen peroxide (H2O2), we showed that H2O2 selectively increases PI3K delta activity while decreasing that of other class I PI3Ks. Blocking PI3K delta activity with a PI3K delta inhibitor or small interfering RNA-mediated PI3K delta gene silencing inhibited HCC-cell proliferation and dampened key features of malignant HCC, including the up-regulation of telomerase reverse transcriptase (TERT). Mechanistically, H2O2 induced oxidative modification of the serpin peptidase inhibitor, serpin peptidase inhibitor (SERPINA3), blocking its ubiquitin-dependent degradation and enhancing its activity as a transcriptional activator of PI3K delta and TERT. High PI3K delta levels in HCC were found to correlate with poor survival rates, with human advanced HCC showing positive correlations between the protein levels of oxidized SERPINA3, PI3K delta, and TERT. Thus, PI3K delta plays significant roles in malignant liver tumors. Conclusion: Our data identify PI3K delta inhibition, recently approved for the treatment of human B-cell malignancies, as a potential treatment for HCC.