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The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness
Journal article   Open access   Peer reviewed

The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness

Chellappagounder Thangavel, Ettickan Boopathi, Steve Ciment, Yi Liu, Raymond O'Neill, Ankur Sharma, Steve B McMahon, Hestia Mellert, Sankar Addya, Adam Ertel, …
Clinical cancer research, v 20(21), pp 5468-5482
01 Nov 2014
PMID: 25165096
url
https://europepmc.org/articles/pmc4216759View
Accepted (AM)Open Access (License Unspecified) Open
url
https://doi.org/10.1158/1078-0432.CCR-14-0326View
Published, Version of Record (VoR) Open

Abstract

Animals Apoptosis - genetics Cell Cycle - genetics Cell Line, Tumor Cell Survival - genetics DNA Damage - genetics DNA Repair - genetics Gene Expression Regulation, Neoplastic - genetics Humans Male Mice Mice, Nude NF-kappa B - genetics Prostatic Neoplasms, Castration-Resistant - genetics Radiation Tolerance - genetics Retinoblastoma - genetics Retinoblastoma Protein - genetics Tumor Suppressor Protein p53 - genetics
Perturbations in the retinoblastoma pathway are over-represented in advanced prostate cancer; retinoblastoma loss promotes bypass of first-line hormone therapy. Conversely, preliminary studies suggested that retinoblastoma-deficient tumors may become sensitized to a subset of DNA-damaging agents. Here, the molecular and in vivo consequence of retinoblastoma status was analyzed in models of clinical relevance. Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of retinoblastoma using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts. Loss of retinoblastoma enhanced the radioresponsiveness of both hormone-sensitive and castrate-resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. Retinoblastoma loss led to alteration in DNA damage repair and activation of the NF-κB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of retinoblastoma-deficient tumors exhibited diminished tumor mass, lower PSA kinetics, and decreased tumor growth after treatment with ionizing radiation (P < 0.05). Loss of retinoblastoma confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of retinoblastoma loss, but also credential retinoblastoma status as a putative biomarker for predicting response to radiotherapy.

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Collaboration types
Domestic collaboration
Web of Science research areas
Oncology
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