title: Pachastrissamine from Pachastrissa sp. inhibits melanoma cell growth by dual inhibition of Cdk2 and ERK-mediated FOXO3 downregulation.
abstract: Melanoma cells are relatively resistant to apoptosis compared with other tumor cell types, and thus, chemotherapy, radiotherapy and immunotherapy are not effective in treating melanoma. Pachastrissamine (PA) exhibits cytotoxic activity and promotes apoptosis in several cancer cells. However, its specific molecular mechanisms have not been characterized fully. This study investigated the antimelanoma effect of PA, an anhydrophytosphingosine derived from marine sponge, and its underlying molecular mechanisms. The data demonstrated that treatment with PA inhibited the phosphorylation of ERK and subsequent ERK-mediated FOXO3 phosphorylation in melanoma cells. Interestingly, PA did not inhibit AKT-mediated FOXO3 phosphorylation. Therefore, it appears that PA-induced apoptosis results from the inhibition of ERK. Furthermore, intravenous administration of PA was found to suppress melanoma cell growth in a C57BL6 mouse without causing side effects. Additionally, PA inhibited the production of Cdk2, which is involved in cell cycle regulation. Taken together, inhibition of melanoma cell growth by PA is a result of the inhibition of ERK-mediated FOXO3 downregulation and decreased Cdk2 levels. The results of this study imply that dual inhibition of the ERK pathway and cell cycle progression could be an effective approach to control the growth of melanoma cells.
authors.affiliation: Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul 137-040, South Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Yoo
authors.forename: Yun Sang
authors.initials: YS
authors.lastname: Lee
authors.forename: Sukjin
authors.initials: S
authors.lastname: Lee
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.forename: Tae-Yoon
authors.initials: TY
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D015536:Down-Regulation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011161:Porifera / Q000737:chemistry; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C468594:pachastrissamine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D013110:Sphingosine