title: Intracellular signaling pathways regulating radioresistance of human prostate carcinoma cells.
abstract: Radiation therapy plays an important role in the management of prostate carcinoma. However, the problem of radioresistance and molecular mechanisms by which prostate carcinoma cells overcome cytotoxic effects of radiation therapy remains to be elucidated. In order to investigate possible intracellular mechanisms underlying the prostate carcinoma recurrences after radiotherapy, we have established three radiation-resistant prostate cancer cell lines, LNCaP-IRR, PC3-IRR, and Du145-IRR derived from the parental LNCaP, PC3, and Du145 prostate cancer cells by repetitive exposure to ionizing radiation. LNCaP-IRR, PC3-IRR, and Du145-IRR cells (prostate carcinoma cells recurred after radiation exposure (IRR cells)) showed higher radioresistance and cell motility than parental cell lines. IRR cells exhibited higher levels of androgen and epidermal growth factor (EGF) receptors and activation of their downstream pathways, such as Ras-mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3-kinase (PI3K)-Akt and Jak-STAT. In order to define additional mechanisms involved in the radioresistance development, we determined differences in the proteome profile of parental and IRR cells using 2-D DIGE followed by computational image analysis and MS. Twenty-seven proteins were found to be modulated in all three radioresistant cell lines compared to parental cells. Identified proteins revealed capacity to interact with EGF and androgen receptors related signal transduction pathways and were involved in the regulation of intracellular routs providing cell survival, increased motility, mutagenesis, and DNA repair. Our data suggest that radioresistance development is accompanied by multiple mechanisms, including activation of cell receptors and related downstream signal transduction pathways. Identified proteins regulated in the radioresistant prostate carcinoma cells can significantly intensify activation of intracellular signaling that govern cell survival, growth, proliferation, invasion, motility, and DNA repair. In addition, such analyses may be utilized in predicting cellular response to radiotherapy.
authors.affiliation: Department of Therapeutic Radiology and Oncology, Innsbruck Medical University, Innsbruck, Austria. ira.skvortsova@i-med.ac.at
authors.forename: Ira
authors.initials: I
authors.lastname: Skvortsova
authors.forename: Sergej
authors.initials: S
authors.lastname: Skvortsov
authors.forename: Taras
authors.initials: T
authors.lastname: Stasyk
authors.forename: Uma
authors.initials: U
authors.lastname: Raju
authors.forename: Bela-Andre
authors.initials: BA
authors.lastname: Popper
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schiestl
authors.forename: Elisabeth
authors.initials: E
authors.lastname: von Guggenberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Neher
authors.forename: Guenther K
authors.initials: GK
authors.lastname: Bonn
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Huber
authors.forename: Peter
authors.initials: P
authors.lastname: Lukas
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival / Q000528:radiation effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020543:Proteome / Q000378:metabolism*; D034741:RNA, Small Interfering; D011836:Radiation Tolerance; D015398:Signal Transduction; D014162:Transfection; D014410:Tumor Stem Cell Assay
chemical_list: D020543:Proteome; D034741:RNA, Small Interfering; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase