Abstract
Kaempferol, a flavonoid, found in traditional medicine, fruits, and vegetables, and an HDAC inhibitor, is a powerful anti-cancer reagent against various cancer cell lines. However, detailed mechanisms involved in the treatment of gastric cancer (GC) using kaempferol are not fully understood. In our study, we investigated the biological activity and molecular mechanism involved in kaempferol-mediated treatment of GC. Kaempferol promoted autophagy and cell death, and increased LC3-I to LC3-II conversion and the downregulation of p62 in GC. Furthermore, our results showed that kaempferol induces autophagic cell death via the activation of the IRE1-JNK-CHOP signaling, indicating ER stress response. Indeed, the inhibition of ER stress suppressed kaempferol-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further showed that kaempferol mediates epigenetic change via the inhibition of G9a (HDAC/G9a axis) and also activates autophagic cell death. Taken together, our findings indicate that kaempferol activates the IRE1-JNK-CHOP signaling from cytosol to nucleus, and G9a inhibition activates autophagic cell death in GC cells.
Highlights
Kaempferol is a natural flavonoid that is widely found in many fruits, vegetables, and traditional herbal medicine[1]
Effects of kaempferol in gastric cancer (GC) cell lines To investigate the cytotoxic effect of kaempferol in GC, we measured the changes of cell viability by kaempferol using WST-1 assay on indicated concentration (Fig. 1a)
GC cells treated with cisplatin or paclitaxel in combination with kaempferol showed lower cell viability than those treated with only cisplatin or paclitaxel
Summary
Kaempferol is a natural flavonoid that is widely found in many fruits, vegetables, and traditional herbal medicine[1]. Kaempferol was recently reported to have anti-cancer properties against several cancers, including gastric, breast, lung, and renal cancer[2,3,4,5]. Flavonoids including kaempferol, quercetin, luteonin, and apigenin potentially function as HDAC inhibitors[6,7]. HDAC inhibitors induce cell death via diverse mechanisms, such as apoptosis, endoplasmic reticulum (ER) stress, autophagy, and epigenetic modification, and they have recently been suggested to be powerful cancer therapeutic agents[8,9,10,11]. Research for anti-cancer effect by kaempferol indicates that it may inhibit the proliferation and expression of and Bcl-2, and upregulation of Bax in HeLa cells and GC cells, implying that it has a therapeutic potential via antitumor effect[2,13]. On the basis of the reported molecular mechanisms, kaempferol, owing to its tumor-inhibiting properties, may be a potential chemotherapeutic strategy
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