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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
A role for neurotensin in bicalutamide resistant prostate cancer cells
Maria Vias1, Glyn Burtt, Zoran Culig
1Department of Oncology, Hutchison/MRC Research Centre, CRUK Uro-Oncology Group, University of Cambridge, Hills Road, Cambridge, United Kingdom.
Background:
Anti-androgens are administered as a principal treatment for prostate cancer. Aggressive hormone refractory disease is characterized in some cases by the development of a neuroendocrine phenotype. However little attention has been paid to resistance pathways selected for by long-term treatment with non-steroidal anti-androgens.
Methods:
Using a resistant sub-line, LNCaP-Bic, we performed a comparative gene expression profiling using cDNA microarrays and target validation by qRT-PCR. Targets were then explored using cell proliferation, cell cycle analysis and in vitro invasion assays using siRNA technology.
Results:
Neurotensin/Neuromedin N (NTS) was upregulated in the LNCaP-Bic line at both the transcript and protein level. The resistant line was found to have an increased proliferation rate, more rapid cell cycle progression and increased invasiveness through Matrigel. Each phenotypic difference could be reduced using siRNA knockdown of NT.
Conclusion:
Increased expression of NT in bicalutamide resistant prostate cancer cells induces cell proliferation and invasion suggesting that this peptide may contribute to the development of bicalutamide resistant prostate cancer.
Insights
Neurotensin (NT) is upregulated in bicalutamide-resistant prostate cancer, driving increased cell proliferation and invasion. This suggests NT may play a key role in the development of treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Anti-androgen therapy is a primary treatment for prostate cancer.
- Hormone-refractory prostate cancer can develop a neuroendocrine phenotype.
- Resistance pathways to non-steroidal anti-androgens are not well understood.
Purpose of the Study:
- To investigate gene expression changes associated with non-steroidal anti-androgen resistance in prostate cancer.
- To identify potential therapeutic targets for overcoming treatment resistance.
Main Methods:
- Comparative gene expression profiling of a resistant prostate cancer cell line (LNCaP-Bic) using cDNA microarrays.
- Target validation via quantitative reverse transcription PCR (qRT-PCR).
- Functional validation using cell proliferation, cell cycle, and invasion assays with siRNA knockdown.
Main Results:
- Neurotensin (NTS) was significantly upregulated at both transcript and protein levels in the resistant cell line.
- The resistant cells exhibited increased proliferation, accelerated cell cycle progression, and enhanced Matrigel invasion.
- siRNA-mediated knockdown of NTS reversed these phenotypic changes.
Conclusions:
- Upregulation of Neurotensin (NT) in bicalutamide-resistant prostate cancer cells promotes proliferation and invasion.
- NT may be a contributing factor to the development of resistance to bicalutamide therapy.
- Targeting NT could be a potential strategy to overcome bicalutamide resistance in prostate cancer.
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