Ircinin-1 induces cell cycle arrest and apoptosis in SK-MEL-2 human melanoma cells
Hye Joung Choi
Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea
Search for more papers by this authorCorresponding Author
Yung Hyun Choi
Department of Biochemistry, College of Oriental Medicine, and Research Center for Oriental Medicine, Dong-Eui University, Busan, South Korea
Yung Hyun Choi, Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-054, South Korea (Y.H.C.).
Nam Deuk Kim, Department of Pharmacy, Pusan National University, Busan 609-735, South Korea (N.D.K.).
Search for more papers by this authorSu-Bog Yee
Research Institute of Genetic Engineering, Pusan National University, Busan, South Korea
Search for more papers by this authorEunok Im
Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea
Search for more papers by this authorJee Hyung Jung
Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea
Search for more papers by this authorCorresponding Author
Nam Deuk Kim
Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea
Yung Hyun Choi, Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-054, South Korea (Y.H.C.).
Nam Deuk Kim, Department of Pharmacy, Pusan National University, Busan 609-735, South Korea (N.D.K.).
Search for more papers by this authorHye Joung Choi
Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea
Search for more papers by this authorCorresponding Author
Yung Hyun Choi
Department of Biochemistry, College of Oriental Medicine, and Research Center for Oriental Medicine, Dong-Eui University, Busan, South Korea
Yung Hyun Choi, Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-054, South Korea (Y.H.C.).
Nam Deuk Kim, Department of Pharmacy, Pusan National University, Busan 609-735, South Korea (N.D.K.).
Search for more papers by this authorSu-Bog Yee
Research Institute of Genetic Engineering, Pusan National University, Busan, South Korea
Search for more papers by this authorEunok Im
Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea
Search for more papers by this authorJee Hyung Jung
Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea
Search for more papers by this authorCorresponding Author
Nam Deuk Kim
Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea
Yung Hyun Choi, Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-054, South Korea (Y.H.C.).
Nam Deuk Kim, Department of Pharmacy, Pusan National University, Busan 609-735, South Korea (N.D.K.).
Search for more papers by this authorAbstract
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-γ1, 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. © 2005 Wiley-Liss, Inc.
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