Capsaicin inhibits the Wnt/β-catenin signaling pathway by down-regulating PP2A.
Xenopus embryo serves as an ideal model for teratogenesis assays to examine the effects of any substances on the cellular processes critical for early development and adult tissue homeostasis. In our chemical library screening with frog embryo, capsaicin was found to repress the Wnt/β-catenin signaling. Depending on the stages at which embryos became exposed to capsaicin, it could disrupt formation of dorsal or posterior body axis of embryo, which is associated with inhibition of maternal or zygotic Wnt signal in early development. In agreement with these phenotypes, capsaicin suppressed the expression of Wnt target genes such as Siamois and Chordin in the organizer region of embryo and in Wnt signals-stimulated tissue explants. In addition, the cellular level of β-catenin, a key component of Wnt pathway, was down-regulated in capsaicin-treated embryonic cells. Unlike wild-type β-catenin, its non-phosphorylatable mutant in which serine and threonine residues phosphorylated by GSK3 are substituted with alanine was not destabilized by capsaicin, indicative of the effect of this chemical on the phosphorylation status of β-catenin. In support of this, capsaicin up-regulated the level of GSK3- or CK1-phosphorylated β-catenin, concomitantly lowering that of its de-phosphorylated version. Notably, capsaicin augmented the phosphorylation of a phosphatase, PP2A at tyrosine 307, suggesting its repression of the enzymatic activity of the phosphatase. Furthermore, capsaicin still enhanced β-catenin phosphorylation in cells treated with a GSK3 inhibitor, LiCl but not in those treated with a phosphatase inhibitor, okadaic acid. Together, these results indicate that capsaicin inhibits the patterning of the dorso-ventral and anterior-posterior body axes of embryo by repressing PP2A and thereby down-regulating the Wnt/β-catenin signaling.
Department of Biomedical Sciences, University of Ulsan College of Medicine, Pungnap-Dong, Songpa-Gu, Seoul 138-736, Republic of Korea.
Dong-Seok
DS
Park
Department of Biomedical Sciences, University of Ulsan College of Medicine, Pungnap-Dong, Songpa-Gu, Seoul 138-736, Republic of Korea.
Gang-Ho
GH
Yoon
School of Life Sciences, College of Natural Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address: leeh@knu.ac.kr.
Hyun-Shik
HS
Lee
Department of Biomedical Sciences, University of Ulsan College of Medicine, Pungnap-Dong, Songpa-Gu, Seoul 138-736, Republic of Korea. Electronic address: choisc@amc.seoul.kr.
Sun-Cheol
SC
Choi
D000818:Animals; D019521:Body Patterning / Q000187:drug effects*; D002211:Capsaicin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D013723:Teratogens / Q000633:toxicity*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D014982:Xenopus laevis
D013723:Teratogens; D054648:Protein Phosphatase 2; D002211:Capsaicin
Capsaicin; PP2A; Wnt signaling; Xenopus; β-catenin