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

Guo,Haiqing; Ren,Feng; Zhang,Li; Zhang,Xiangying; Yang,Rongrong; Xie,Bangxiang; Li,Zhuo; Hu,Zhongjie; Duan,Zhongping; Zhang,Jing

doi:10.3892/mmr.2016.4845

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

Authors:
- Haiqing Guo
- Feng Ren
- Li Zhang
- Xiangying Zhang
- Rongrong Yang
- Bangxiang Xie
- Zhuo Li
- Zhongjie Hu
- Zhongping Duan
- Jing Zhang
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Affiliations: Department of Hepatitis C and Drug‑Induced Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China, Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, P.R. China, Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China, Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P.R. China
Published online on: February 2, 2016 https://doi.org/10.3892/mmr.2016.4845
Pages: 2791-2800

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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 HepG2 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.

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