title: Ircinin-1 induces cell cycle arrest and apoptosis in SK-MEL-2 human melanoma cells.
abstract: We investigated the effects of ircinin-1, a lipid compound (a C25 sesterterpene tetronic acid) isolated from marine sponges (Sarcotragus sp.), on the modulation of cell cycle and induction of apoptosis in SK-MEL-2 human skin cancer cells (mutant p53). Ircinin-1 treatment on SK-MEL-2 cells resulted in a dose-dependent inhibition of cell growth and induced apoptotic cell death. Flow cytometric analysis revealed that ircinin-1 resulted in G1 arrest in cell cycle progression which was associated with a marked decrease in the protein expression of D-type cyclins and their activating partners Cdk 4 and 6 with concomitant inductions of p21WAF1/CIP1 and p27KIP1. The induction of p21WAF1/CIP1 appears to be transcriptionally upregulated and is p53-independent. In addition, ircinin-1 suppressed the phosphorylation of pRb protein and increased the co-association of pRb or proliferating cell nuclear antigen (PCNA) with p21WAF1/CIP1 in these cells. Ircinin-1 treatment also resulted in induction of apoptosis as determined by morphological changes, DNA fragmentation, alternated ratio of Bax/Bcl-2, cleavages of poly(ADP-ribose) polymerase and PLC-gamma1, and flow cytometric analysis. Ircinin-1 also induced cytochrome c release, cleavage activations of caspase-3 and -9, and upregulation of Fas and Fas-L. Even though the inhibitor of apoptosis protein (IAP) was expressed in ircinin-1-untreated or -treated SK-MEL-2 cells, only the level of cIAP-1, but not XIAP or cIAP-2, was decreased during ircinin-1-induced apoptosis at Western blot and RT-PCR studies. Taken together, these findings suggest that ircinin-1 has strong potential for development as an agent for prevention against skin cancer.
authors.affiliation: Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea.
authors.forename: Hye Joung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.forename: Su-Bog
authors.initials: SB
authors.lastname: Yee
authors.forename: Eunok
authors.initials: E
authors.lastname: Im
authors.forename: Jee Hyung
authors.initials: JH
authors.lastname: Jung
authors.forename: Nam Deuk
authors.initials: ND
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D053222:Fas Ligand Protein; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D015394:Molecular Structure; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D048069:Tumor Necrosis Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005663:Furans; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; D012717:Sesquiterpenes; D048069:Tumor Necrosis Factors; C506002:ircinin-1; D004247:DNA; D020169:Caspases