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Published on: April 27, 2018
Adenovirus-mediated IKKbetaKA expression sensitizes prostate carcinoma cells to TRAIL-induced apoptosis
A D Sanlioglu1, I T Koksal, B Karacay
1Human Gene Therapy Unit, Akdeniz University, Faculty of Medicine, Antalya, Turkey. sanlioglu@akdeniz.edu.tr
Abstract:
Despite the fact that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells, TRAIL resistance in cancer cells has challenged the use of TRAIL as a therapeutic agent. First, prostate carcinoma cell lines (DU145, LNCaP and PC3) were screened for sensitivity to adenovirus delivery of TRAIL (Ad5hTRAIL). As amplified Ikappa B kinase (IKK) activity is responsible for the constitutive nuclear factor-kappaB (NF-kappaB) activation leading to uncontrolled cell growth and metastasis, a dual vector approach using both an adenovirus vector (Ad) expressing the dominant-negative mutant of IKKbeta (AdIKKbetaKA) and Ad5hTRAIL was employed to determine if prostate cancer cells were sensitized to TRAIL in the setting of IKK inhibition. Inhibition of the NF-kappaB pathway through IKK blockade sensitized all three prostate cancer cell lines to TRAIL, regardless of NF-kappaB activation or decoy receptor gene expression. Moreover, a novel quantitative real-time RT-PCR assay and conventional flow cytometry analysis indicated that TRAIL-resistant DU145 and LNCaP cells, but not TRAIL-sensitive PC3 cells, expressed substantial amounts of TRAIL Decoy Receptor 4. In conclusion, TRAIL decoy receptor expression appeared to be the chief determinant of TRAIL resistance encountered in prostate carcinoma cell lines.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in prostate cancer can be overcome by inhibiting the NF-kappaB pathway. TRAIL Decoy Receptor 4 expression is a key factor determining TRAIL sensitivity in these cells.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells.
- TRAIL resistance in cancer cells limits its therapeutic application.
- Nuclear factor-kappaB (NF-kappaB) pathway activation, driven by amplified Ikappa B kinase (IKK) activity, promotes cancer cell growth and metastasis.
Purpose of the Study:
- To investigate if inhibiting the NF-kappaB pathway sensitizes prostate cancer cells to TRAIL.
- To determine the role of TRAIL Decoy Receptor 4 in TRAIL resistance.
Main Methods:
- Screening of prostate carcinoma cell lines (DU145, LNCaP, PC3) for TRAIL sensitivity using adenovirus delivery (Ad5hTRAIL).
- Employing a dual vector approach with adenovirus expressing a dominant-negative IKKbeta mutant (AdIKKbetaKA) and Ad5hTRAIL.
- Utilizing quantitative real-time RT-PCR and flow cytometry to analyze decoy receptor expression.
Main Results:
- Inhibition of the NF-kappaB pathway via IKK blockade sensitized all tested prostate cancer cell lines to TRAIL.
- TRAIL-resistant DU145 and LNCaP cells expressed substantial amounts of TRAIL Decoy Receptor 4.
- TRAIL-sensitive PC3 cells expressed lower levels of TRAIL Decoy Receptor 4.
Conclusions:
- NF-kappaB pathway inhibition is a viable strategy to overcome TRAIL resistance in prostate cancer.
- TRAIL Decoy Receptor 4 expression is a primary determinant of TRAIL resistance in prostate carcinoma cell lines.
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