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A Novel Primary Cell Line Model of Localized Prostate Cancer and Radioresistance-A Role for Nicotinamide
Jessica A Wright1,2, Stephanie D White1,2, Gavin Frame1,2
1Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada.
Cells
|June 11, 2025
Summary
Researchers developed new prostate cancer cell lines representing localized disease. Targeting NNMT, an enzyme found in tumors, sensitized radioresistant cells to radiation, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Existing prostate cancer cell lines often represent metastatic disease, limiting research on localized tumors.
- There is a need for novel cell line models that better reflect early-stage prostate cancer and its treatment resistance.
Purpose of the Study:
- To develop and characterize a paired set of primary prostate cancer cell lines representing treatment-naïve and radioresistant disease.
- To identify molecular mechanisms underlying radioresistance in prostate cancer.
- To evaluate Nicotinamide N-methyltransferase (NNMT) as a potential therapeutic target for overcoming radioresistance.
Main Methods:
- Derivation of a primary localized prostate cancer cell line (CaB34) from patient tissue.
- Generation of a radioresistant subline (CaB34-CF) using fractionated radiotherapy.
- Multi-omic analyses (RNAseq, shotgun proteomics) to identify molecular differences.
- NNMT knockdown studies using siRNA in cell lines and 3D organoids.
- Assessment of radiosensitization and induction of cellular senescence.
Main Results:
- The CaB34 cell line, derived from localized Gleason 7 prostate cancer, spontaneously immortalized.
- CaB34-CF cells exhibited increased growth in 3D organoids and altered cytokeratin expression compared to CaB34.
- NNMT was identified as significantly upregulated in CaB34-CF and more abundant in prostate tumors.
- NNMT knockdown in CaB34-CF cells led to significant radiosensitization, primarily through increased radiation-induced senescence.
- Radiosensitization by NNMT siRNA was confirmed in a 3D organoid clonogenic assay.
Conclusions:
- The study provides a valuable paired model of localized, treatment-naïve, and radioresistant prostate cancer.
- NNMT is implicated in prostate cancer progression and radioresistance.
- Targeting NNMT demonstrates potential as a therapeutic strategy to sensitize radioresistant prostate cancer to radiotherapy.
