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Nrf2‐Activating Phytochemicals, Sulforaphane and Licochalcone A, Stimulate Cell Growth‐Regulating Kinases in HCT116 Human Colorectal Cancer Cells

Some phytochemicals have been reported to modulate phase II detoxifying/antioxidant enzyme expressions via both Keap1 (Kelch‐like ECH‐associated protein 1)‐dependent and independent regulations of a nuclear factor E2‐related factor 2/antioxidant response element (Nrf2/ARE) system. Based on multiple studies, various kinase signaling pathways are also responsible for regulation of Nrf2/ARE activity differently depending on cell types, microenvironmental factors, treatment doses, etc. Sulforaphane (SFN) and licochalcone A (LicA) are known as potent Nrf2/ARE inducers that can modulate several kinases including phosphoinositide 3‐kinase (PI3K)/Protein kinase B (Akt) and p38 mitogen‐activated protein kinase (MAPK) in propagating cancer cells. The purpose of the present study was to investigate the molecular mechanism through which SFN and LicA can activate Nrf2/ARE system and upregulate heme oxygenase‐1 (HO‐1) expression in HCT116 human colorectal cancer cells. Results revealed that SFN and LicA induced ARE‐transcriptional activity and subsequently increased HO‐1 expression through PI3K and p38 MAPK signaling pathways in HCT116 cells. In addition, HCT116 cell proliferation was significantly promoted when Nrf2/ARE activity was increased by either SFN‐induced PI3K activation or LicA‐induced p38 MAPK activation. These observations indicate that SFN and LicA regulated the Nrf2/ARE/HO‐1 system via phosphorylation of PI3K and p38 MAPK, respectively, in proliferation of HCT116 colorectal cancer cells. In conclusion, the present study highlights the working mechanism of potent Nrf2/ARE activators that possibly perturb the activities of various kinases in the growing cancer cells.