Radioresistance of prostate cancer cells with low proteasome activity

• Published in: The Prostate 2012-06, Vol.72 (8), p.868-874
• Main Authors: Della Donna, Lorenza, Lagadec, Chann, Pajonk, Frank
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Adenocarcinoma - radiotherapy; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Boronic Acids - pharmacology; Boronic Acids - therapeutic use; Bortezomib; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Medical sciences; Mice; Mice, Nude; Nephrology. Urinary tract diseases; Phenotype; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - radiotherapy; proteasome; Proteasome Endopeptidase Complex - metabolism; Pyrazines - pharmacology; Pyrazines - therapeutic use; Radiation Tolerance; radioresistance; Radiotherapy; self-renewal; Treatment Failure; tumorigenicity; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.21489

BACKGROUND Prostate cancer is frequently treated with radiotherapy. While treatment results are in general excellent, some patients relapse and current systemic therapies are not curative, thus, underlining the need for novel targeted therapies. Proteasome inhibitors have been suggested as promising new agents against solid tumors including prostate cancer but initial results from clinical trials are disappointing. METHODS In this study we tested if prostate cancer cells are heterogeneous with regard to their intrinsic 26S proteasome activity, which could explain the lack of clinical responses to bortezomib. PC‐3 and DU145 prostate cancer cells and an imaging system for proteasome activity were used to identify individual cells with low proteasome activity. Clonogenic survival assays, a sphere‐forming assay and an in vivo limiting dilution assay were used to characterize radiation sensitivity, self‐renewal capacity, and tumorigenicity of the different subsets of cells. RESULTS We identified a small population of cells with intrinsically low 26S proteasome activity. Fractionated radiation enriched for these cells and clonogenic survival assays and sphere‐forming assays revealed a radioresistant phenotype and increased self‐renewal capacity. CONCLUSIONS We conclude that low 26S proteasome activity identifies a radioresistant prostate cancer cell population. This population of cells could be responsible for the clinical resistance of advanced prostate cancer to proteasome inhibitors and radiation. Prostate 72:868–874, 2012. © 2011 Wiley Periodicals, Inc.