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Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of
José María Mora-Rodríguez1,2, Belén G Sánchez1,2, Alba Sebastián-Martín1,2
1Biochemistry and Molecular Biology Unit, Department of Systems Biology, School of Medicine and Health Sciences, University of Alcalá, 28871 Alcalá de Henares, Madrid, Spain.
Abstract:
In this study, we examined the metabolic adaptations of a chemoresistant prostate cancer cell line in comparison to a sensitive cell line. We utilized prostate cancer LNCaP cells and subjected them to a stepwise increase in the antiandrogen 2-hydroxy-flutamide (FLU) concentration to generate a FLU-resistant cell line (LN-FLU). These LN-FLU cells displayed characteristics of cancer stem cells, exhibited drug resistance, and showed a significantly reduced expression of Cyclin D1, along with the overexpression of p16, pointing to a proliferation arrest. In comparing the cancer stem-like LN-FLU cells to the LNCaP cells, we observed a decrease in the expression of CTP-choline cytidylyl transferase α (CCTα), as well as a decline in choline kinase, suggesting altogether a downregulation of the phosphatidylcholine biosynthetic pathway. In addition, we found decreased levels of the protein methyl transferase PRMT2 and the upregulation of the histone deacetylase Sirtuin1 (Sirt1). Analysis of the human prostate cancer samples revealed similar results in a population with high expressions of the stem cell markers Oct4 and ABCB1A1. Our findings suggest that the adaptation of prostate cancer cells to antiandrogens could induce reprogramming into stem cells that survive in a low phosphocholine metabolism and cell cycle arrest and display drug resistance.
Insights
Chemoresistant prostate cancer cells adapt by becoming stem-like, entering cell cycle arrest, and altering metabolism. This reprogramming leads to reduced phosphocholine metabolism and increased drug resistance.
Area of Science:
- Oncology
- Cancer Biology
- Metabolic Adaptations
Background:
- Prostate cancer cells develop chemoresistance.
- Understanding metabolic adaptations is crucial for overcoming resistance.
Purpose of the Study:
- To investigate metabolic and cellular changes in chemoresistant prostate cancer cells.
- To compare chemoresistant cells with sensitive counterparts.
Main Methods:
- Generated a 2-hydroxy-flutamide (FLU)-resistant prostate cancer cell line (LN-FLU) from LNCaP cells.
- Analyzed cell characteristics, drug resistance, and expression of key proteins (Cyclin D1, p16, CCTα, choline kinase, PRMT2, Sirt1).
- Examined human prostate cancer samples for stem cell marker expression (Oct4, ABCB1A1).
Main Results:
- LN-FLU cells exhibited cancer stem cell traits and drug resistance.
- Reduced Cyclin D1 and increased p16 indicated proliferation arrest.
- Downregulation of phosphatidylcholine biosynthesis pathway observed (decreased CCTα and choline kinase).
- Altered expression of PRMT2 and Sirtuin1 (Sirt1) noted.
- Similar metabolic and stem cell marker patterns found in human prostate cancer samples.
Conclusions:
- Antiandrogen adaptation can reprogram prostate cancer cells into drug-resistant stem cells.
- These adapted cells feature low phosphocholine metabolism and cell cycle arrest.
- Findings suggest novel therapeutic targets for overcoming prostate cancer chemoresistance.
