KLF4 mediates the contradictory effects of phenylethyl isothiocyanate in gastric cancer intervention

Abstract

Phenethyl isothiocyanate (PEITC) exerts anti-gastric cancer effect, however, the molecular mechanism has not yet been elucidated. KLF4 is an important regulatory molecule in gastric cancer. The programmed death ligand 1 (PD-L1) interacts with programmed cell death 1 (PD-1), inhibits function of cytotoxic T-lymphocyte and helps gastric cancer cells evade immune surveillance. The present study aimed to investigate the effect of PEITC against gastric cancer and the roles of KLF4 and PD-L1 in the anti-gastric cancer effect of PEITC. The effects of PEITC on gastric cancer cell proliferation and apoptosis were detected by EdU assay, flow cytometric analysis, immunoblotting and in vivo xenograft tumor experiment. The expression of KLF4 and PD-L1 was examined in PEITC-treated gastric cancer cells using immunoblotting, immunofluorescence and flow cytometric analysis. Co-culture system was used to assess the cancer cell-killing effect of PEITC combined with anti-PD-L1 blockade in gastric cancer. The results showed that PEITC suppressed cell activities both in vitro and in vivo. PEITC upregulated the expression of KLF4, which suppressed cyclin D1 expression and activated Bax expression, and mediated the growth inhibition effect of PEITC in gastric cancer. Meanwhile, we found that KLF4 induced by PEITC transcriptionally activated PD-L1 expression and diminished anti-cancer effects of anti-PD-L1 therapy in gastric cancer cells. Findings from this research revealed that PEITC restricted gastric cancer cell growth through activating KLF4. PEITC attenuated anti-PD-L1 therapy efficacy attributing to KLF4-upregulated PD-L1. These results uncover a novel mechanism of PEITC in gastric cancer intervention.

Keywords: Gastric cancer; KLF4; PD-L1; Phenethyl isothiocyanate.