Zhang Qi, Yang Chenying, Zhou Bei, Gao Xingsu, Zhong Caiyun, Shi Ye, Cao Hui, Zhu Mingming
Department of Public Health, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Yinzhou Center for Disease Control and Prevention, Ningbo, 315000, China.
Med Oncol. 2025 Jun 12;42(7):253. doi: 10.1007/s12032-025-02795-1.
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.
异硫氰酸苯乙酯（PEITC）具有抗胃癌作用，但其分子机制尚未阐明。KLF4是胃癌中的一种重要调节分子。程序性死亡配体1（PD-L1）与程序性细胞死亡蛋白1（PD-1）相互作用，抑制细胞毒性T淋巴细胞的功能，帮助胃癌细胞逃避免疫监视。本研究旨在探讨PEITC对胃癌的作用以及KLF4和PD-L1在PEITC抗胃癌作用中的作用。通过EdU检测、流式细胞术分析、免疫印迹和体内异种移植肿瘤实验检测PEITC对胃癌细胞增殖和凋亡的影响。采用免疫印迹、免疫荧光和流式细胞术分析检测PEITC处理的胃癌细胞中KLF4和PD-L1的表达。利用共培养系统评估PEITC联合抗PD-L1阻断对胃癌细胞的杀伤作用。结果表明，PEITC在体外和体内均抑制细胞活性。PEITC上调KLF4的表达，抑制细胞周期蛋白D1的表达并激活Bax的表达，介导PEITC对胃癌的生长抑制作用。同时，我们发现PEITC诱导的KLF4转录激活PD-L1的表达，并减弱抗PD-L1治疗对胃癌细胞的抗癌作用。本研究结果表明，PEITC通过激活KLF4抑制胃癌细胞生长。由于KLF4上调PD-L1，PEITC减弱了抗PD-L1治疗的疗效。这些结果揭示了PEITC在胃癌干预中的新机制。
