title: PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways.
abstract: The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins. We also demonstrated that compared with combination of single PI3K or mTOR inhibitors (BKM120 or Rapamycin) and radiation, low-dose of dual PI3K/mTOR inhibitors (BEZ235 or PI103) combined with radiation greatly improved treatment efficacy by repressing colony formation, inducing more apoptosis, leading to the arrest of the G2/M phase, increased double-strand break levels and less inactivation of cell cycle check point, autophagy and non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathway proteins in CaP-radioresistant cells. This study describes the possible pathways associated with CaP radioresistance and demonstrates the putative mechanisms of the radiosensitization effect in CaP-resistant cells in the combination treatment. The findings from this study suggest that the combination of dual PI3K/Akt/mTOR inhibitors (BEZ235 or PI103) with radiotherapy is a promising modality for the treatment of CaP to overcome radioresistance.
authors.affiliation: 1] Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, SESLHD, Kogarah, New South Wales 2217, Australia [2] Faculty of Medicine, St. George and Sutherland Clinical School, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Chang
authors.affiliation: 1] Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, SESLHD, Kogarah, New South Wales 2217, Australia [2] Faculty of Medicine, St. George and Sutherland Clinical School, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: P H
authors.initials: PH
authors.lastname: Graham
authors.affiliation: 1] Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, SESLHD, Kogarah, New South Wales 2217, Australia [2] Faculty of Medicine, St. George and Sutherland Clinical School, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Hao
authors.affiliation: 1] Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, SESLHD, Kogarah, New South Wales 2217, Australia [2] Faculty of Medicine, St. George and Sutherland Clinical School, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Ni
authors.affiliation: 1] Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, SESLHD, Kogarah, New South Wales 2217, Australia [2] Faculty of Medicine, St. George and Sutherland Clinical School, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Bucci
authors.affiliation: 1] Faculty of Medicine, St. George and Sutherland Clinical School, University of New South Wales, Kensington, New South Wales 2052, Australia [2] Department of Surgery, St. George Hospital, Kogarah, New South Wales 2217, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Cozzi
authors.affiliation: 1] Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, SESLHD, Kogarah, New South Wales 2217, Australia [2] Faculty of Medicine, St. George and Sutherland Clinical School, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: J H
authors.initials: JH
authors.lastname: Kearsley
authors.affiliation: 1] Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, SESLHD, Kogarah, New South Wales 2217, Australia [2] Faculty of Medicine, St. George and Sutherland Clinical School, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001343:Autophagy; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D059766:DNA End-Joining Repair / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D059765:Homologous Recombination / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology* / Q000532:radiotherapy; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human