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Ircinin-1 induces cell cycle arrest and apoptosis in SK-MEL-2 human melanoma cells
Hye Joung Choi1, Yung Hyun Choi, Su-Bog Yee
1Department of Pharmacy and Pusan Cancer Research Center, Pusan National University, Busan, South Korea.
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.
Insights
Ircinin-1, a marine sponge compound, inhibits skin cancer cell growth by inducing cell cycle arrest and apoptosis. This compound shows potential for skin cancer prevention by modulating key cell cycle proteins and apoptotic pathways.
Area of Science:
- Marine Natural Products Chemistry
- Cancer Biology
- Pharmacology
Background:
- Ircinin-1 is a C25 sesterterpene tetronic acid isolated from marine sponges.
- SK-MEL-2 human skin cancer cells possess mutant p53, a common feature in many cancers.
- Understanding the mechanisms of novel compounds is crucial for cancer therapeutics.
Purpose of the Study:
- To investigate the effects of ircinin-1 on cell cycle modulation and apoptosis induction in SK-MEL-2 cells.
- To elucidate the molecular pathways targeted by ircinin-1 in skin cancer cells.
Main Methods:
- Cell treatment with ircinin-1
- Flow cytometry for cell cycle analysis
- Western blot and RT-PCR for protein and gene expression analysis
- Assays for apoptosis induction (morphological changes, DNA fragmentation, caspase activation)
Main Results:
- Ircinin-1 caused dose-dependent inhibition of cell growth and induced apoptosis in SK-MEL-2 cells.
- G1 cell cycle arrest was observed, linked to decreased D-type cyclins/Cdk4/6 and increased p21WAF1/CIP1/p27KIP1.
- Apoptosis was mediated by cytochrome c release, caspase activation, altered Bax/Bcl-2 ratio, and decreased cIAP-1 levels.
- p21WAF1/CIP1 induction was p53-independent and transcriptionally upregulated.
Conclusions:
- Ircinin-1 effectively inhibits skin cancer cell proliferation and induces apoptosis through p53-independent mechanisms.
- The compound modulates cell cycle regulators and apoptotic signaling pathways.
- Ircinin-1 demonstrates significant potential as a therapeutic agent for skin cancer prevention.
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