Sp Nipin, Kang Dong Young, Jo Eun Seong, Lee Jin-Moo, Bae Se Won, Jang Kyoung-Jin
Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Chungju, South Korea.
Pharmacological Research Division, National Institute of Food and Drug Safety Evaluation, Osong Health Technology Administration Complex, Cheongju-si, South Korea.
Front Oncol. 2021 Nov 3;11:781720. doi: 10.3389/fonc.2021.781720. eCollection 2021.
Embryonic cancer stem cells (CSCs) can differentiate into any cancer type. Targeting CSCs with natural compounds is a promising approach as it suppresses cancer recurrence with fewer adverse effects. 6-Gingerol is an active component of ginger, which exhibits well-known anti-cancer activities. This study determined the mechanistic aspects of cell death induction by 6-gingerol. To analyze cellular processes, we used Western blot and real-time qPCR for molecular signaling studies and conducted flow cytometry. Our results suggested an inhibition of CSC marker expression and Wnt/β-catenin signaling by 6-gingerol in NCCIT and NTERA-2 cells. 6-Gingerol induced reactive oxygen species generation, the DNA damage response, cell cycle arrest, and the intrinsic pathway of apoptosis in embryonic CSCs. Furthermore, 6-gingerol inhibited iron metabolism and induced PTEN, which both played vital roles in the induction of cell death. The activation of PTEN resulted in the inhibition of PD-L1 expression through PI3K/AKT/p53 signaling. The induction of PTEN also mediated the downregulation of microRNAs miR-20b, miR-21, and miR-130b to result in PD-L1 suppression by 6-gingerol. Hence, 6-gingerol may be a promising candidate to target CSCs by regulating PTEN-mediated PD-L1 expression.
胚胎癌干细胞（CSCs）可分化为任何癌症类型。用天然化合物靶向CSCs是一种很有前景的方法，因为它能抑制癌症复发且副作用较少。6-姜酚是生姜的一种活性成分，具有众所周知的抗癌活性。本研究确定了6-姜酚诱导细胞死亡的机制。为了分析细胞过程，我们使用蛋白质免疫印迹法和实时定量聚合酶链反应进行分子信号研究，并进行了流式细胞术检测。我们的结果表明，6-姜酚在NCCIT和NTERA-2细胞中抑制了CSC标志物的表达以及Wnt/β-连环蛋白信号传导。6-姜酚在胚胎CSCs中诱导活性氧生成、DNA损伤反应、细胞周期停滞和凋亡的内在途径。此外，6-姜酚抑制铁代谢并诱导PTEN，这两者在细胞死亡诱导中都起着至关重要的作用。PTEN的激活通过PI3K/AKT/p53信号传导导致PD-L1表达的抑制。PTEN的诱导还介导了微小RNA miR-20b、miR-21和miR-130b的下调，从而导致6-姜酚对PD-L1的抑制。因此，6-姜酚可能是通过调节PTEN介导的PD-L1表达来靶向CSCs的一个有前景的候选物。
