Dataset Information

Prodigiosin down-regulates SKP2 to induce p27(KIP1) stabilization and antiproliferation in human lung adenocarcinoma cells.

ABSTRACT:

Background and purpose

High levels of SKP2 are a poor prognostic factor in multiple human cancers and mostly correlate with low p27(KIP1) 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-p27(KIP1) axis in prodigiosin's cytostatic effect on human lung adenocarcinoma cells.

Experimental approach

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.

Key results

Prodigiosin increased p27(KIP1) expression mainly by stabilizing p27(KIP1) through transcriptional repression of SKP2. Importantly, SKP2 overexpression or p27(KIP1) 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-3?. 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 prodigiosin-treated cells.

Conclusions and implications

Transcriptional repression of SKP2 and the consequent accumulation of p27(KIP1) are essential for prodigiosin's antiproliferative action. Mechanistically, prodigiosin induces PKB inhibition to down-regulate SKP2 in a GSK-3?- and E2F1-independent manner. Our findings further implicate the potential for developing prodigiosin as a novel class of SKP2-targeting anticancer agent.

SUBMITTER: Hsieh HY

PROVIDER: S-EPMC3402774 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Prodigiosin down-regulates SKP2 to induce p27(KIP1) stabilization and antiproliferation in human lung adenocarcinoma cells.

Hsieh Hsin-Ying HY Shieh Jeng-Jer JJ Chen Chun-Jung CJ Pan Mu-Yun MY Yang Shu-Yi SY Lin Shin-Chang SC Chang Jo-Shu JS Lee Alan Yueh-Luen AY Chang Chia-Che CC

British journal of pharmacology 20120801 7

<h4>Background and purpose</h4>High levels of SKP2 are a poor prognostic factor in multiple human cancers and mostly correlate with low p27(KIP1) 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-p27(KIP1) axis in prodigiosin's cytostatic effect on human lung adenocarcinoma cells.<h4>Exp ...[more]

PMID: 22372491

Similar Datasets

Project description:BACKGROUND: p27(kip1) is a tumour suppressor gene, functioning as a cyclin-dependent kinase inhibitor, and an independent prognostic factor in breast, colon, and prostate adenocarcinomas. Conflicting data are reported for adenocarcinoma of the pancreas. The aim of this study was to establish the prognostic value of p27(kip1) expression in adenocarcinoma of the pancreatic head region. PATIENTS AND METHODS: The study included 45 patients (male/female ratio 2:1; mean age 59, range 38-82 years) with adenocarcinomas of the pancreatic head region: 24 - pancreatic head, 18 - periampullary and 3 - uncinate process. The patients underwent the Kausch-Whipple pancreatoduodenectomy (n=39), pylorus-preserving pancreatoduodenectomy (n=5), or nearly total pancreatectomy (n=1). Eight patients received adjuvant chemotherapy postoperatively. Follow-up time ranged from 3 to 60 months. Tumours were staged according to the pTNM classification (UICC 1997). Immunohistochemistry was done on paraffin-embedded blocks from tumour sections. Quantitative determination of p27(kip1) expression was based on the proportion of p27(kip1) -positive cells (< 5% = negative). Survival analysis was carried out using the Kaplan-Meier method and Cox regression model. RESULTS: Positive p27(kip1) expression was detected in 22 tumours (49%), whereas 23 tumours (51%) were p27(kip1)-negative. There were no significant correlations between p27(kip1) index and stage or lymph node involvement. Median survival time in patients with p27(kip1)-positive tumours was 19 months, whereas in patients with p27(kip1)-negative tumours it was 18 months (p=0.53). A significant relationship was found between p27(kip1)-negative tumours and radical resection (p=0.04). Multivariate survival analysis revealed that the localization of the tumour (pancreatic head/uncinate process vs periampullary) was the only significant and independent prognosticator (p = 0.01, Cox regression model). Resection margins involvement and grade remained nearly significant prognostic factors (p=0.07 and p=0.09, respectively). CONCLUSION: We conclude that p27(kip1) has limited overall prognostic utility in resected carcinoma of the pancreatic head region, but its potential role as a marker of residual disease needs to be further assessed.

Dataset Information

Prodigiosin down-regulates SKP2 to induce p27(KIP1) stabilization and antiproliferation in human lung adenocarcinoma cells.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Prodigiosin down-regulates SKP2 to induce p27(KIP1) stabilization and antiproliferation in human lung adenocarcinoma cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets