title: Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance.
abstract: Radioresistance is a major challenge in prostate cancer (CaP) radiotherapy (RT). In this study, we investigated the role and association of epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and the PI3K/Akt/mTOR signaling pathway in CaP radioresistance. We developed three novel CaP radioresistant (RR) cell lines (PC-3RR, DU145RR and LNCaPRR) by radiation treatment and confirmed their radioresistance using a clonogenic survival assay. Compared with untreated CaP-control cells, the CaP-RR cells had increased colony formation, invasion ability and spheroid formation capability (P<0.05). In addition, enhanced EMT/CSC phenotypes and activation of the checkpoint proteins (Chk1 and Chk2) and the PI3K/Akt/mTOR signaling pathway proteins were also found in CaP-RR cells using immunofluorescence, western blotting and quantitative real-time PCR (qRT-PCR). Furthermore, combination of a dual PI3K/mTOR inhibitor (BEZ235) with RT effectively increased radiosensitivity and induced more apoptosis in CaP-RR cells, concomitantly correlated with the reduced expression of EMT/CSC markers and the PI3K/Akt/mTOR signaling pathway proteins compared with RT alone. Our findings indicate that CaP radioresistance is associated with EMT and enhanced CSC phenotypes via activation of the PI3K/Akt/mTOR signaling pathway, and that the combination of BEZ235 with RT is a promising modality to overcome radioresistance in the treatment of CaP. This combination approach warrants future in vivo animal study and clinical trials.
authors.affiliation: 1] Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, Gray St. Kogarah, Sydney, New South Wales 2217, Australia [2] St. George Clinical School, Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Chang
authors.forename: P H
authors.initials: PH
authors.lastname: Graham
authors.forename: J
authors.initials: J
authors.lastname: Hao
authors.forename: J
authors.initials: J
authors.lastname: Ni
authors.forename: J
authors.initials: J
authors.lastname: Bucci
authors.forename: P J
authors.initials: PJ
authors.lastname: Cozzi
authors.forename: J H
authors.initials: JH
authors.lastname: Kearsley
authors.forename: Y
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000532:radiotherapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib