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Accepted (AM)Open Access (License Unspecified), Open
Journal article
The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness
Clinical cancer research, v 20(21), pp 5468-5482
01 Nov 2014
PMID: 25165096
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness
- Creators
- Chellappagounder Thangavel - Thomas Jefferson UniversityEttickan Boopathi - Department of Surgery, Division of Urology, Glenolden, Pennsylvania, USA.Steve Ciment - Thomas Jefferson UniversityYi Liu - Thomas Jefferson UniversityRaymond O'Neill - Thomas Jefferson UniversityAnkur Sharma - Thomas Jefferson UniversitySteve B McMahon - Thomas Jefferson UniversityHestia Mellert - University of Colorado BoulderSankar Addya - Thomas Jefferson UniversityAdam Ertel - Sidney Kimmel Cancer CenterRuth Birbe - Thomas Jefferson UniversityPaolo Fortina - Thomas Jefferson UniversityAdam P Dicker - Thomas Jefferson UniversityKaren E Knudsen - Kimmel Cancer CenterRobert B Den - Thomas Jefferson University
- Publication Details
- Clinical cancer research, v 20(21), pp 5468-5482
- Publisher
- American Association for Cancer Research (AACR)
- Grant note
- P30 CA056036 / NCI NIH HHS R01 CA176401 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000344759100016
- Scopus ID
- 2-s2.0-84908700892
- Other Identifier
- 991019176648304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology