skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Ku70, Ku80, and sClusterin: A Cluster of Predicting Factors for Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer

Abstract

Purpose: The identification of predictive biomarkers for neoadjuvant chemoradiation therapy (CRT) is a current clinical need. The heterodimer Ku70/80 plays a critical role in DNA repair and cell death induction after damage. The aberrant expression and localization of these proteins fail to control DNA repair and apoptosis. sClusterin is the Ku70 partner that sterically inhibits Bax-dependent cell death after damage in some pathologic conditions. This study sought to evaluate the molecular relevance of Ku70-Ku80-Clu as a molecular cluster predicting the response to neoadjuvant CRT in patients with locally advanced rectal cancer (LARC). Methods and Materials: Patients enrolled in this study underwent preoperative CRT followed by surgical excision. A retrospective study based on individual response, evaluated by computed tomography and diffusion-weighted magnetic resonance imaging, identified responder (56%) and no-responder patients (44%). Ku70/80 and Clu expression were observed in biopsy specimens obtained before and after treatment with neoadjuvant CRT from the same LARC patients. In vitro studies before and after irradiation were also performed on radioresistant (SW480) and radiosensitive (SW620) colorectal cancer cell lines, mimicking sensitive or resistant tumor behavior. Results: We found a conventional nuclear localization of Ku70/80 in pretherapeutic tumor biopsies of responder patients, in agreement with their role in DNAmore » repair and regulating apoptosis. By contrast, in the no-responder population we observed an unconventional overexpression of Ku70 in the cytoplasm (P<.001). In this context we also overexpression of sClu in the cytoplasm, which accorded with its role in stabilizing of Bax-Ku70 complex, inhibiting Bax-dependent apoptosis. Strikingly, Ku80 in these tumor tissues was lost (P<.005). In vitro testing of colon cancer cells finally confirmed the results observed in tumor biopsy specimens, proving that Ku70/80-Clu deregulation is extensively involved in the resistance mechanism. Conclusion: These results strongly suggest a potential role of these proteins as a new prognostic tool to predict the response to chemoradiation in LARC.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
OSTI Identifier:
22645777
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 97; Journal Issue: 2; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANIMAL TISSUES; APOPTOSIS; BIOLOGICAL MARKERS; BIOPSY; CHEMOTHERAPY; COMPUTERIZED TOMOGRAPHY; DNA REPAIR; IN VITRO; MAGNETIC RESONANCE; NEOPLASMS; NMR IMAGING; PATIENTS; RECTUM

Citation Formats

Pucci, Sabina, E-mail: sabina.pucci@uniroma2.it, Polidoro, Chiara, Joubert, Alessandro, Mastrangeli, Francesca, Tolu, Barbara, Benassi, Michaela, Fiaschetti, Valeria, Greco, Laura, Miceli, Roberto, Floris, Roberto, Novelli, Giuseppe, Orlandi, Augusto, and Santoni, Riccardo. Ku70, Ku80, and sClusterin: A Cluster of Predicting Factors for Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer. United States: N. p., 2017. Web. doi:10.1016/J.IJROBP.2016.10.018.
Pucci, Sabina, E-mail: sabina.pucci@uniroma2.it, Polidoro, Chiara, Joubert, Alessandro, Mastrangeli, Francesca, Tolu, Barbara, Benassi, Michaela, Fiaschetti, Valeria, Greco, Laura, Miceli, Roberto, Floris, Roberto, Novelli, Giuseppe, Orlandi, Augusto, & Santoni, Riccardo. Ku70, Ku80, and sClusterin: A Cluster of Predicting Factors for Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer. United States. doi:10.1016/J.IJROBP.2016.10.018.
Pucci, Sabina, E-mail: sabina.pucci@uniroma2.it, Polidoro, Chiara, Joubert, Alessandro, Mastrangeli, Francesca, Tolu, Barbara, Benassi, Michaela, Fiaschetti, Valeria, Greco, Laura, Miceli, Roberto, Floris, Roberto, Novelli, Giuseppe, Orlandi, Augusto, and Santoni, Riccardo. Wed . "Ku70, Ku80, and sClusterin: A Cluster of Predicting Factors for Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer". United States. doi:10.1016/J.IJROBP.2016.10.018.
@article{osti_22645777,
title = {Ku70, Ku80, and sClusterin: A Cluster of Predicting Factors for Response to Neoadjuvant Chemoradiation Therapy in Patients With Locally Advanced Rectal Cancer},
author = {Pucci, Sabina, E-mail: sabina.pucci@uniroma2.it and Polidoro, Chiara and Joubert, Alessandro and Mastrangeli, Francesca and Tolu, Barbara and Benassi, Michaela and Fiaschetti, Valeria and Greco, Laura and Miceli, Roberto and Floris, Roberto and Novelli, Giuseppe and Orlandi, Augusto and Santoni, Riccardo},
abstractNote = {Purpose: The identification of predictive biomarkers for neoadjuvant chemoradiation therapy (CRT) is a current clinical need. The heterodimer Ku70/80 plays a critical role in DNA repair and cell death induction after damage. The aberrant expression and localization of these proteins fail to control DNA repair and apoptosis. sClusterin is the Ku70 partner that sterically inhibits Bax-dependent cell death after damage in some pathologic conditions. This study sought to evaluate the molecular relevance of Ku70-Ku80-Clu as a molecular cluster predicting the response to neoadjuvant CRT in patients with locally advanced rectal cancer (LARC). Methods and Materials: Patients enrolled in this study underwent preoperative CRT followed by surgical excision. A retrospective study based on individual response, evaluated by computed tomography and diffusion-weighted magnetic resonance imaging, identified responder (56%) and no-responder patients (44%). Ku70/80 and Clu expression were observed in biopsy specimens obtained before and after treatment with neoadjuvant CRT from the same LARC patients. In vitro studies before and after irradiation were also performed on radioresistant (SW480) and radiosensitive (SW620) colorectal cancer cell lines, mimicking sensitive or resistant tumor behavior. Results: We found a conventional nuclear localization of Ku70/80 in pretherapeutic tumor biopsies of responder patients, in agreement with their role in DNA repair and regulating apoptosis. By contrast, in the no-responder population we observed an unconventional overexpression of Ku70 in the cytoplasm (P<.001). In this context we also overexpression of sClu in the cytoplasm, which accorded with its role in stabilizing of Bax-Ku70 complex, inhibiting Bax-dependent apoptosis. Strikingly, Ku80 in these tumor tissues was lost (P<.005). In vitro testing of colon cancer cells finally confirmed the results observed in tumor biopsy specimens, proving that Ku70/80-Clu deregulation is extensively involved in the resistance mechanism. Conclusion: These results strongly suggest a potential role of these proteins as a new prognostic tool to predict the response to chemoradiation in LARC.},
doi = {10.1016/J.IJROBP.2016.10.018},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 2,
volume = 97,
place = {United States},
year = {Wed Feb 01 00:00:00 EST 2017},
month = {Wed Feb 01 00:00:00 EST 2017}
}