Kaempferol induces apoptosis in HepG2 cells via activation of the endoplasmic reticulum stress pathway

Abstract

Kaempferol is a flavonoid compound that has gained importance due to its antitumor properties; however, the underlying mechanisms remain to be fully understood. The present study aimed to investigate the molecular mechanisms of the antitumor function of kaempferol in HepG, 2 hepatocellular carcinoma cells. Kaempferol was determined to reduce cell viability, increase lactate dehydrogenase activity and induce apoptosis in a concentration- and time-dependent manner in HepG2 cells. Additionally, kaempferol-induced apoptosis possibly acts via the endoplasmic reticulum (ER) stress pathway, due to the significant increase in the protein expression levels of glucose-regulated protein 78, glucose-regulated protein 94, protein kinase R-like ER kinase, inositol-requiring enzyme 1α, partial activating transcription factor 6 cleavage, caspase-4, C/EBP homologous protein (CHOP) and cleaved caspase-3. The pro-apoptotic activity of kaempferol was determined to be due to induction of the ER stress-CHOP pathway, as: i) ER stress was blocked by 4-phenyl butyric acid (4-PBA) pretreatment and knockdown of CHOP with small interfering RNA, which resulted in alleviation of kaempferol-induced HepG2 cell apoptosis; and ii) transfection with plasmid overexpressing CHOP reversed the protective effect of 4-PBA in kaempferol-induced HepG2 cells and increased the apoptotic rate. Thus, kaempferol promoted HepG2 cell apoptosis via induction of the ER stress-CHOP signaling pathway. These observations indicate that kaempferol may be used as a potential chemopreventive treatment strategy for patients with hepatocellular carcinoma.