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A Rapid Filter Insert-based 3D Culture System for Primary Prostate Cell Differentiation
Published on: February 13, 2017
TRAIL-DISC formation is androgen-dependent in the human prostatic carcinoma cell line LNCaP
Oskar W Rokhlin1, Agshin F Taghiyev, Nataliya V Guseva
1Department of Pathology, The University of Iowa, Iowa City, Iowa 52242, USA.
Abstract:
We and others have previously described that the androgen-responsive human prostatic carcinoma cell line LNCaP is resistant to TRAIL and that TRAIL-mediated apoptosis in LNCaP is PI3K/Akt-dependent. In this study, we found that LNCaP remained resistant to treatment with TRAIL after androgen deprivation even in the presence of the PI3K/Akt pathway inhibitor wortmannin. This resistance was determined by failure to form the TRAIL-DISC and by decreased TRAIL-R1 and TRAIL-R2 levels after androgen deprivation; the capacity of TRAIL to induce DISC formation was completely restored in the presence of DHT. TRAIL and wortmannin together accelerated processing of caspase-8 on the DISC and apparently the release of caspase-8 from the DISC into the cytoplasm. Surprisingly, we found that wortmannin decreased the total amount of TRAIL-R1, but not TRAIL-R2, in the cells as well as the amount of TRAIL-R1 precipitated by TRAIL. Our data suggest that TRAIL-DISC formation and sensitivity to TRAIL treatment are androgen-dependent in LNCaP.
Insights
Androgen deprivation in prostate cancer cells (LNCaP) maintains resistance to TRAIL-induced apoptosis, even with PI3K/Akt pathway inhibition. Androgen signaling is crucial for TRAIL receptor expression and DISC formation, impacting cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- The human prostatic carcinoma cell line LNCaP is known to be resistant to TRAIL-mediated apoptosis.
- TRAIL-induced apoptosis in LNCaP cells is dependent on the PI3K/Akt pathway.
Purpose of the Study:
- To investigate the role of androgen deprivation in TRAIL resistance in LNCaP cells.
- To elucidate the mechanisms underlying androgen-dependent TRAIL sensitivity.
Main Methods:
- LNCaP cells were treated with TRAIL and wortmannin (a PI3K/Akt inhibitor) under androgen-deprived conditions.
- Analysis of TRAIL-DISC formation, TRAIL receptor levels (TRAIL-R1, TRAIL-R2), and caspase-8 processing.
- Assessment of androgen (DHT) restoration effects on TRAIL sensitivity.
Main Results:
- LNCaP cells remained resistant to TRAIL after androgen deprivation, irrespective of PI3K/Akt inhibition.
- Androgen deprivation led to impaired TRAIL-DISC formation and reduced TRAIL-R1/TRAIL-R2 levels.
- Dihydrotestosterone (DHT) restored TRAIL-induced DISC formation.
- Wortmannin decreased TRAIL-R1 levels and accelerated caspase-8 processing on the DISC.
Conclusions:
- TRAIL-DISC formation and sensitivity to TRAIL treatment are androgen-dependent in LNCaP cells.
- Androgen signaling is critical for maintaining TRAIL receptor expression and facilitating TRAIL-induced apoptosis in prostate cancer cells.
