(+)-2-(1-Hydroxyl-4-oxocyclohexyl) ethyl caffeate suppresses solar UV-induced skin carcinogenesis by targeting PI3K, ERK1/2, and p38.
For decades, skin cancer incidence has increased, mainly because of 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 (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 Cl41 cells without toxicity. PI3K, 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 PI3K, ERK1/2, and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP1 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 a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure.
The Hormel Institute, University of Minnesota, Austin, Minnesota;
Do Young
DY
Lim
The Hormel Institute, University of Minnesota, Austin, Minnesota;
Mee-Hyun
MH
Lee
The Hormel Institute, University of Minnesota, Austin, Minnesota; Program in Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, Minnesota.
Seung Ho
SH
Shin
The Hormel Institute, University of Minnesota, Austin, Minnesota;
Hanyoung
H
Chen
The Hormel Institute, University of Minnesota, Austin, Minnesota;
Joohyun
J
Ryu
Department of Natural Product Chemistry, Second Military Medical University;
Lei
L
Shan
School of Pharmacy, East China University of Science & Technology, Shanghai, PR China; and.
Honglin
H
Li
The Hormel Institute, University of Minnesota, Austin, Minnesota;
Ann M
AM
Bode
Department of Natural Product Chemistry, Second Military Medical University; zgdong@hi.umn.edu wdzhangy@hotmail.com.
Wei-Dong
WD
Zhang
The Hormel Institute, University of Minnesota, Austin, Minnesota; zgdong@hi.umn.edu wdzhangy@hotmail.com.
Zigang
Z
Dong
D000255:Adenosine Triphosphate / Q000378:metabolism; D000287:Administration, Topical; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry*; D001665:Binding Sites; D001667:Binding, Competitive; D002109:Caffeic Acids / Q000737:chemistry*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000737:chemistry*; D004817:Epidermis / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010936:Plant Extracts / Q000378:metabolism; D010944:Plants / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D014466:Ultraviolet Rays / Q000009:adverse effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C000597303:2-(1-hydroxy-4-oxocyclohexyl)ethyl caffeate; D016588:Anticarcinogenic Agents; D002109:Caffeic Acids; D003512:Cyclohexanones; D010936:Plant Extracts; C032773:ethyl caffeate; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases