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Title: Intensified autophagy compromises the efficacy of radiotherapy against prostate cancer

Abstract

Introduction: Radiotherapy is an equivalent alternative or complement to radical prostatectomy, with high therapeutic efficacy. High risk patients, however, experience high relapse rates, so that research on radio-sensitization is the most evident route to improve curability of this common disease. Materials and methods: In the current study we investigated the autophagic activity in a series of patients with localized prostate tumors treated with radical radiotherapy, using the LC3A and the LAMP2a proteins as markers of autophagosome and lysosome cellular content, respectively. The role of autophagy on prostate cancer cell line resistance to radiation was also examined. Results: Using confocal microscopy on tissue biopsies, we showed that prostate cancer cells have, overall, high levels of LC3A and low levels of LAMP2a compared to normal prostate glands. Tumors with a ‘highLC3A/lowLAMP2a’ phenotype, suggestive of intensified lysosomal consumption, had a significantly poorer biochemical relapse free survival. The PC3 radioresistant cell line sustained remarkably its autophagic flux ability after radiation, while the DU145 radiosensitive one experiences a prolonged blockage of the autophagic process. This was assessed with aggresome accumulation detection and LC3A/LAMP2a double immunofluorescence, as well as with sequestrosome/p62 protein detection. By silencing the LC3A or LAMP2a expression, both cell lines became more sensitivemore » to escalated doses of radiation. Conclusions: High base line autophagy activity and cell ability to sustain functional autophagy define resistance of prostate cancer cells to radiotherapy. This can be reversed by blocking up-regulated components of the autophagy pathway, which may prove of importance in the field of clinical radiotherapy. - Highlights: • High LC3A and low LAMP2a levels is a frequent expression pattern of prostate carcinoma. • This pattern of intensified autophagic flux relates with high relapse rates after radiotherapy. • The PC3 radio-resistant cell line sustains remarkably its autophagic flux ability after radiation. • Irradiation of the DU145 radio-sensitive cell line blocks the autophagic flux. • Intense autophagy activity defines prostate cancer radio-resistance, in vivo and in vitro.« less

Authors:
; ; ;  [1]; ;  [2]
  1. Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis, 68100 (Greece)
  2. Department of Pathology, Democritus University of Thrace, Alexandroupolis, 68100 (Greece)
Publication Date:
OSTI Identifier:
22462058
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 461; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; BIOPSY; BUILDUP; CARCINOMAS; DETECTION; IN VITRO; IN VIVO; IRRADIATION; MICROSCOPY; PATIENTS; PHENOTYPE; PROSTATE; RADICALS; RADIOSENSITIVITY; RADIOTHERAPY

Citation Formats

Koukourakis, Michael I., E-mail: targ@her.forthnet.gr, Kalamida, Dimitra, Mitrakas, Achilleas, Pouliliou, Stamatia, Kalamida, Sofia, Sivridis, Efthimios, and Giatromanolaki, Alexandra. Intensified autophagy compromises the efficacy of radiotherapy against prostate cancer. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.04.014.
Koukourakis, Michael I., E-mail: targ@her.forthnet.gr, Kalamida, Dimitra, Mitrakas, Achilleas, Pouliliou, Stamatia, Kalamida, Sofia, Sivridis, Efthimios, & Giatromanolaki, Alexandra. Intensified autophagy compromises the efficacy of radiotherapy against prostate cancer. United States. doi:10.1016/J.BBRC.2015.04.014.
Koukourakis, Michael I., E-mail: targ@her.forthnet.gr, Kalamida, Dimitra, Mitrakas, Achilleas, Pouliliou, Stamatia, Kalamida, Sofia, Sivridis, Efthimios, and Giatromanolaki, Alexandra. Fri . "Intensified autophagy compromises the efficacy of radiotherapy against prostate cancer". United States. doi:10.1016/J.BBRC.2015.04.014.
@article{osti_22462058,
title = {Intensified autophagy compromises the efficacy of radiotherapy against prostate cancer},
author = {Koukourakis, Michael I., E-mail: targ@her.forthnet.gr and Kalamida, Dimitra and Mitrakas, Achilleas and Pouliliou, Stamatia and Kalamida, Sofia and Sivridis, Efthimios and Giatromanolaki, Alexandra},
abstractNote = {Introduction: Radiotherapy is an equivalent alternative or complement to radical prostatectomy, with high therapeutic efficacy. High risk patients, however, experience high relapse rates, so that research on radio-sensitization is the most evident route to improve curability of this common disease. Materials and methods: In the current study we investigated the autophagic activity in a series of patients with localized prostate tumors treated with radical radiotherapy, using the LC3A and the LAMP2a proteins as markers of autophagosome and lysosome cellular content, respectively. The role of autophagy on prostate cancer cell line resistance to radiation was also examined. Results: Using confocal microscopy on tissue biopsies, we showed that prostate cancer cells have, overall, high levels of LC3A and low levels of LAMP2a compared to normal prostate glands. Tumors with a ‘highLC3A/lowLAMP2a’ phenotype, suggestive of intensified lysosomal consumption, had a significantly poorer biochemical relapse free survival. The PC3 radioresistant cell line sustained remarkably its autophagic flux ability after radiation, while the DU145 radiosensitive one experiences a prolonged blockage of the autophagic process. This was assessed with aggresome accumulation detection and LC3A/LAMP2a double immunofluorescence, as well as with sequestrosome/p62 protein detection. By silencing the LC3A or LAMP2a expression, both cell lines became more sensitive to escalated doses of radiation. Conclusions: High base line autophagy activity and cell ability to sustain functional autophagy define resistance of prostate cancer cells to radiotherapy. This can be reversed by blocking up-regulated components of the autophagy pathway, which may prove of importance in the field of clinical radiotherapy. - Highlights: • High LC3A and low LAMP2a levels is a frequent expression pattern of prostate carcinoma. • This pattern of intensified autophagic flux relates with high relapse rates after radiotherapy. • The PC3 radio-resistant cell line sustains remarkably its autophagic flux ability after radiation. • Irradiation of the DU145 radio-sensitive cell line blocks the autophagic flux. • Intense autophagy activity defines prostate cancer radio-resistance, in vivo and in vitro.},
doi = {10.1016/J.BBRC.2015.04.014},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 2,
volume = 461,
place = {United States},
year = {2015},
month = {5}
}