title: Radioresistance of prostate cancer cells with low proteasome activity.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 LeConte Ave., Los Angeles, CA 90095-1714, USA.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Della Donna
authors.forename: Chann
authors.initials: C
authors.lastname: Lagadec
authors.forename: Frank
authors.initials: F
authors.lastname: Pajonk
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D011836:Radiation Tolerance; D011878:Radiotherapy; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease