(+)-2-(1-Hydroxyl-4-oxocyclohexyl) ethyl caffeate suppresses solar UV-induced skin carcinogenesis by targeting PI3-K, ERK1/2 and p38
Menée sur des lignées cellulaires et à l'aide d'un modèle murin, cette étude montre qu'un composé dérivé du caféate d'éthyle peut inhiber la carcinogenèse de la peau induite par les ultraviolets en bloquant l'activité des kinases PI3-K, ERK1/2 et p38
For decades, skin cancer incidence has increased, mainly due to oncogenic signaling pathways activated by solar ultraviolet (UV) irradiation (i.e., sun exposure). Solar UV induces multiple signaling pathways that are critical in the development of skin cancer, and therefore the development of compounds capable of targeting multiple molecules for chemoprevention of skin carcinogenesis is urgently needed. Herein, we examined the chemopreventive effects and the molecular mechanism of HOEC, [(+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate], isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 C14l cells without toxicity. PI3-K, ERK1/2 and p38 kinase activities were suppressed by direct binding with HOEC in vitro. Our in silico docking data showed that HOEC binds at the ATP-binding site of each kinase. The inhibition of solar UV-induced PI3-K, ERK1/2 and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP-1 and NF-κB transactivation in JB6 cells. Furthermore, topical application of HOEC reduced skin cancer incidence and tumor volume in SKH-1 hairless mice chronically exposed to solar UV. In summary, our results show that HOEC exerts inhibitory effects on multiple kinase targets and their downstream pathways activated by solar UV in vitro and in vivo. These findings suggest that HOEC is as a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure.