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Stromal anti-apoptotic androgen receptor target gene c-FLIP in prostate cancer
Huihui Ye1, Yirong Li, Jonathan Melamed
1Department of Pathology and Urology, New York University School of Medicine, New York Harbor Healthcare System, New York, New York 10010, USA.
Purpose:
The tumor microenvironment significantly influences prostate cancer progression. Androgen receptor exerts its effect through downstream target genes to regulate prostate cancer cell proliferation. The c-FLIP gene was recently shown to be an androgen receptor target gene. c-FLIP is an inactive homologue of caspase-8 and, thus, it inhibits the death receptor mediated apoptosis pathway. c-FLIP over expression was shown to accelerate the progression of prostate cancer cells to androgen independence. We evaluated the role of c-FLIP expression in stromal cells in prostate cancer development.
Materials And Methods:
We examined c-FLIP expression in 53 androgen dependent and 21 androgen independent prostate cancer stromal cells by immunohistochemical analysis. The effects of c-FLIP over expression in stromal cells on the growth and invasion of LNCaP and PC3 prostate cancer cells were determined in indirect coculture systems.
Results:
At the androgen dependent stage the stromal c-FLIP level was increased in prostate cancer tissue. The expression level of stromal c-FLIP was associated with tumor differentiation. However, stromal c-FLIP expression was not increased in androgen independent human prostate cancer. c-FLIP over expression in stromal cells stimulated the growth and invasion of prostate cancer, including LNCaP and PC3 cells in vitro.
Conclusions:
These results indicate the over expression of stromal c-FLIP and its function for promoting prostate cancer growth and invasion.
Insights
Stromal c-FLIP (cellular FLICE-inhibitory protein) is elevated in early prostate cancer, promoting tumor growth and invasion. Its role diminishes as cancer becomes androgen-independent.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The tumor microenvironment critically impacts prostate cancer progression.
- Androgen receptor signaling regulates prostate cancer cell proliferation via target genes.
- Cellular FLICE-inhibitory protein (c-FLIP) is an androgen receptor target gene inhibiting apoptosis and promoting androgen independence.
Purpose of the Study:
- To investigate the role of c-FLIP expression in prostate cancer stromal cells.
- To determine the association between stromal c-FLIP and prostate cancer development and progression.
Main Methods:
- Immunohistochemical analysis of c-FLIP expression in 53 androgen-dependent and 21 androgen-independent prostate cancer stromal cells.
- In vitro coculture systems to assess the impact of stromal c-FLIP overexpression on prostate cancer cell growth and invasion (LNCaP and PC3 cells).
Main Results:
- Stromal c-FLIP levels were increased in androgen-dependent prostate cancer tissue and correlated with tumor differentiation.
- Stromal c-FLIP expression was not elevated in androgen-independent prostate cancer.
- Overexpression of c-FLIP in stromal cells enhanced the in vitro growth and invasion of prostate cancer cells.
Conclusions:
- Stromal c-FLIP is overexpressed in early-stage prostate cancer.
- Stromal c-FLIP promotes prostate cancer cell growth and invasion.
- The role of stromal c-FLIP may be more significant in androgen-dependent disease.
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