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FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN
Vijayanand Modur1, Rakesh Nagarajan, B Mark Evers
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
Mutations in PTEN occur in 60-80% of prostate cancers and lead to a constitutive activation of the phosphatidylinositol 3-kinase pathway and a resultant loss of activity of the FOXO family of forkhead transcription factors FKHRL1 and FKHR. To provide insight into the role of PTEN mutations in prostate cancer, we used microarrays to identify genes regulated by FKHRL1 and FKHR in LAPC4 prostate carcinoma cells. These studies revealed that adenoviral overexpression of FKHRL1 and FKHR in the LAPC4 prostate cancer cell line resulted in apoptosis and induced the expression of many genes that affect cellular proliferation or survival. The expression of one of these FOXO-regulated genes, TRAIL, a pro-apoptotic member of the tumor necrosis factor family, was decreased in human metastatic prostate tumors. The altered expression of TRAIL in these tumors correlated directly with decreased PTEN expression and the resultant loss of FKHRL1 and FKHR activity. Analysis of the effects of FOXO proteins on the TRAIL promoter localized the FKHRL1 responsive element of the TRAIL promoter to nucleotides -138 to -121 and demonstrated that TRAIL is a direct target of FKHRL1. These findings suggest that the decreased activity of FKHRL1 and FKHR in prostate cancers resulting from loss of PTEN leads to a decrease in TRAIL expression that may contribute to increased survival of the tumor cells.
Insights
Loss of PTEN in prostate cancer reduces FOXO activity, decreasing TRAIL expression and promoting tumor cell survival. This study identifies TRAIL as a direct target of FOXO transcription factors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PTEN mutations are common in prostate cancer, activating the PI3K pathway and inhibiting FOXO transcription factors (FKHRL1, FKHR).
- FOXO proteins regulate genes involved in cell proliferation and survival.
Purpose of the Study:
- To investigate the role of PTEN mutations in prostate cancer by identifying genes regulated by FKHRL1 and FKHR.
- To understand the impact of FOXO activity on tumor progression.
Main Methods:
- Microarray analysis was used to identify genes regulated by FKHRL1 and FKHR in LAPC4 prostate cancer cells.
- Adenoviral overexpression of FKHRL1 and FKHR was performed.
- TRAIL promoter analysis was conducted to identify regulatory elements.
Main Results:
- Overexpression of FKHRL1 and FKHR induced apoptosis and upregulated genes affecting cell proliferation/survival.
- TRAIL, a pro-apoptotic gene, was downregulated in metastatic prostate tumors, correlating with decreased PTEN and FOXO activity.
- FKHRL1 directly targets the TRAIL promoter, with a responsive element located at nucleotides -138 to -121.
Conclusions:
- Decreased PTEN activity in prostate cancer leads to reduced FKHRL1/FKHR activity.
- This results in decreased TRAIL expression, potentially contributing to prostate tumor cell survival.