Open AccessWithaferin A suppresses tumor promoter 12‐ O ‐tetradecanoylphorbol 13‐acetate‐induced decreases in isocitrate dehydrogenase 1 activity and mitochondrial function in skin epidermal JB 6 cells
Author(s) -
Li Wenjuan,
Zhao Yunfeng
Publication year - 2013
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12051
Subject(s) - 12 o tetradecanoylphorbol 13 acetate , withaferin a , isocitrate dehydrogenase , carcinogenesis , tumor promotion , biology , mitochondrion , microbiology and biotechnology , cell growth , chemistry , withania somnifera , biochemistry , cancer research , phosphorylation , medicine , pathology , enzyme , phorbol ester , alternative medicine , protein kinase c , gene
Withaferin A ( WA ) is a bioactive compound derived from W ithania somnifera . The antitumor activity of WA has been well studied in human cancer models; however, its chemopreventive potential is unclear. In the present study, we used the skin epidermal JB 6 P + cells, a well‐established model for tumor promotion, and demonstrated that WA suppressed the tumor promoter 12‐ O ‐tetradecanoylphorbol 13‐acetate ( TPA )‐induced cell transformation and cell proliferation. Interestingly, TPA inactivated isocitrate dehydrogenase 1 ( IDH 1), which was reversed by WA . Similar results were also observed in mouse skin tissue. Therefore, we focused on metabolism as the potential mechanism of action. We found that mitochondrial functions were downregulated by TPA treatment, as indicated by reduced mitochondrial membrane potential, complex I activity and mitochondrial respiration. However, all of these downregulations were inhibited by WA . In addition, we examined the levels of α‐ketoglutarate, a product of IDH 1, and WA blocked its reduction upon TPA treatment. Finally, we detected the lactate level as a glycolysis marker, and WA suppressed its elevation caused by tumor promoter treatment. Altogether, these results suggest that WA might exert its chemopreventive activity via inhibiting not only oncogenic activation, but also IDH 1 inactivation and mitochondrial dysfunction in early tumorigenesis.