Dataset Information

Prostacyclin inhibits non-small cell lung cancer growth by a frizzled 9-dependent pathway that is blocked by secreted frizzled-related protein 1.

ABSTRACT: The goal of this study was to assess the ability of iloprost, an orally active prostacyclin analog, to inhibit transformed growth of human non-small cell lung cancer (NSCLC) and to define the mechanism of iloprost's tumor suppressive effects. In a panel of NSCLC cell lines, the ability of iloprost to inhibit transformed cell growth was not correlated with the expression of the cell surface receptor for prostacyclin, but instead was correlated with the presence of Frizzled 9 (Fzd 9) and the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma). Silencing of Fzd 9 blocked PPARgamma activation by iloprost, and expression of Fzd 9 in cells lacking the protein resulted in iloprost's activation of PPARgamma and inhibition of transformed growth. Interestingly, soluble Frizzled-related protein-1, a well-known inhibitor of Wnt/Fzd signaling, also blocked the effects of iloprost and Fzd 9. Moreover, mice treated with iloprost had reduced lung tumors and increased Fzd 9 expression. These studies define a novel paradigm, linking the eicosanoid pathway and Wnt signaling. In addition, these data also suggest that prostacyclin analogs may represent a new class of therapeutic agents in the treatment of NSCLC where the restoration of noncanonical Wnt signaling maybe important for the inhibition of transformed cell growth.

SUBMITTER: Tennis MA

PROVIDER: S-EPMC2838442 | biostudies-other | 2010 Mar

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Prostacyclin inhibits non-small cell lung cancer growth by a frizzled 9-dependent pathway that is blocked by secreted frizzled-related protein 1.

Tennis Meredith A MA Van Scoyk Michelle M Heasley Lynn E LE Vandervest Katherine K Weiser-Evans Mary M Freeman Scott S Keith Robert L RL Simpson Pete P Nemenoff Raphael A RA Winn Robert A RA

Neoplasia (New York, N.Y.) 20100301 3

The goal of this study was to assess the ability of iloprost, an orally active prostacyclin analog, to inhibit transformed growth of human non-small cell lung cancer (NSCLC) and to define the mechanism of iloprost's tumor suppressive effects. In a panel of NSCLC cell lines, the ability of iloprost to inhibit transformed cell growth was not correlated with the expression of the cell surface receptor for prostacyclin, but instead was correlated with the presence of Frizzled 9 (Fzd 9) and the activ ...[more]

PMID: 20234818

Similar Datasets

Project description:BackgroundRecent studies indicate that long noncoding RNAs (lncRNAs) play a key role in the control of cellular processes such as proliferation, metastasis, and differentiation. The lncRNA dysregulation has been identified in all types of cancer. We previously found that lncRNA AK126698 suppresses cisplatin resistance in A549 cells through the Wnt/β-catenin signaling pathway. However, the clinical significance of lncRNA AK126698 and the molecular mechanisms through which it regulates cancer cell proliferation and migration are largely unknown.MethodsWe examined the expression of lncRNA AK126698 in 56 non-small cell lung cancer (NSCLC) tissue samples and three NSCLC cell lines using quantitative real-time polymerase chain reaction. Gain and loss of function approaches were used to evaluate the biological function of AK126698 in NSCLC cells. The effects of lncRNA AK126698 on cell proliferation were investigated using cell counting kit-8 and 5-ethynyl-2'-deoxyuridine assays, and apoptosis was measured by flow cytometry. Protein levels of AK126698 targets were evaluated by Western blotting.ResultsOur results showed that lncRNA AK126698 was significantly downregulated in NSCLC tissues, compared with paired adjacent nontumor tissue samples. Furthermore, lower AK126698 expression was associated with larger tumor size and advanced tumor stage. Ectopic AK126698 expression inhibited cell proliferation and migration and induced apoptosis. Conversely, decreased AK126698 expression promoted cell proliferation and migration and inhibited cell apoptosis. Importantly, we demonstrated that Frizzled-8, a receptor of Wnt/β-catenin pathway, was a target of AK126698. Furthermore, AK126698 could inhibit the activation of Wnt/β-catenin pathway, which was demonstrated by measuring the expression levels of Axin1, β-catenin, c-myc, cyclin D1, and E-cadherin.ConclusionIt was found in the study that lncRNA AK126698 inhibits the proliferation and migration of NSCLC cells by targeting Frizzled-8 to suppress the Wnt/β-catenin signaling pathway. It may provide a new target for therapeutic intervention in NSCLC.

Project description:Secreted frizzled-related proteins (SFRPs) as Wnt signaling antagonists have been found to be dysregulated by promoter hypermethylation in several cancers including acute myeloid leukemia (AML). This study aimed to investigate the methylated status of SFRPs promoter region and its clinical relevance in Chinese non-M3 AML patients.SFRPs methylation in 139 primary non-M3 AML patients was determined using methylation-specific real-time quantitative polymerase chain reaction.The frequency of aberrant methylation was as follows: 30.2% for SFRP1, 27.3% for SFRP2, 5.0% for SFRP4, and 1.4% for SFRP5. Hypermethylation of at least one SFRP gene occurred in 51.8% (72/139) of non-M3 AML patient samples, which was significantly higher compared to normal control (0/21) (P<0.001). Hypermethylation of SFRP1 was potentially associated with N/K-RAS mutations (P=0.043), and the frequency of SFRPs methylation was higher in patients ≥50 years compared to those <50 years, especially for SFRP2 (P<0.05). Furthermore, both whole cohort and cytogenetically normal (CN) patients with high SFRPs-methylated group showed a shorter overall survival (OS) compared to those with low group (P=0.036 and P=0.035, respectively). Moreover, Cox regression multivariate analysis revealed that SFRPs hypermethylation acts as an independent prognostic biomarker among both whole cohort (hazard ratio =1.804, P=0.026) and CN (hazard ratio =2.477, P=0.023) patients. In leukemic cell line HL60 treated with 5-aza-2'-deoxycytidine, the alteration of SFRP1/2 expression inversely correlated with change in SFRP1/2 methylation (r=-0.975, P=0.005 and r=-0.975, P=0.005, respectively). A tendency of negative correlation was observed between SFRP1 expression and its promoter methylation in AML patients (r=-0.334, P=0.038).These findings suggested that hypermethylation of SFRP1/2 was a frequent event and silenced SFRP1/2 expression in AML. Moreover, hypermethylation of SFRPs promoter was an adverse risk factor for OS in Chinese non-M3 AML patients.

Dataset Information

Prostacyclin inhibits non-small cell lung cancer growth by a frizzled 9-dependent pathway that is blocked by secreted frizzled-related protein 1.

Publications

Prostacyclin inhibits non-small cell lung cancer growth by a frizzled 9-dependent pathway that is blocked by secreted frizzled-related protein 1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets