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|標題:||Prodigiosin down-regulates SKP2 to induce p27KIP1 stabilization and antiproliferation in human lung adenocarcinoma cells||作者:||Hsieh, Hsin-Ying
Lee, Alan Yueh-Luen
|關鍵字:||prodigiosin;SKP2;p27KIP1;AKT;PKB;antiproliferation;lung adenocarcinoma||Project:||British Journal of Pharmacology, Volume 166, page(s) 2095–2108.||摘要:||
BACKGROUND AND PURPOSE:
High levels of SKP2 are a poor prognostic factor in multiple human cancers and mostly correlate with low p27KIP1 levels.
Prodigiosin is a bacterial tripyrrole pigment with strong pro-apoptotic activity. Induction of cell cycle blockade underlies one
of its anticancer actions but the mechanisms involved are unclear. The aim of this study was to explore the role of the
SKP2–p27KIP1 axis in prodigiosin’s cytostatic effect on human lung adenocarcinoma cells.
Prodigiosin’s effects on cell cycle progression and long-term cell proliferation of human lung adenocarcinoma cells were
characterized by flow cytometry and colony formation assay, respectively. Real-time RT-PCR and promoter activity analyses
were performed for assessing transcriptional control, while cycloheximide chase analysis evaluated protein stability.
Immunoblotting was employed for mechanistic study.
Prodigiosin increased p27KIP1 expression mainly by stabilizing p27KIP1 through transcriptional repression of SKP2. Importantly,
SKP2 overexpression or p27KIP1 depletion restored the colony forming capacity of prodigiosin-treated cells. Furthermore,
prodigiosin induced PKB dephosphorylation, leading to PKB inhibition as revealed by decreased serine 9 phosphorylation of
GSK-3b. Constitutive PKB activation reduced prodigiosin-induced SKP2 repression. Prodigiosin also down-regulated E2F1
(mediates PI3K/PKB-induced SKP2 transcription), but E2F1 overexpression failed to restore SKP2 expression in
CONCLUSIONS AND IMPLICATIONS:
Transcriptional repression of SKP2 and the consequent accumulation of p27KIP1 are essential for prodigiosin’s antiproliferative
action. Mechanistically, prodigiosin induces PKB inhibition to down-regulate SKP2 in a GSK-3b- and E2F1-independent
manner. Our findings further implicate the potential for developing prodigiosin as a novel class of SKP2-targeting anticancer
|Appears in Collections:||生物醫學研究所|
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