Title

The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness.

Authors

Chellappagounder Thangavel, Department of Radiation Oncology, Thomas Jefferson University
Ettickan Boopathi, Department of Surgery, Division of Urology, University of Pennsylvania
Steve Ciment, Department of Radiation Oncology, Thomas Jefferson University
Yi Liu, Department of Radiation Oncology, Thomas Jefferson UniversityFollow
Raymond O'Neill, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityFollow
Ankur Sharma, Department of Cancer Biology, Thomas Jefferson University
Steve B McMahon, Department of Cancer Biology, Thomas Jefferson University; Kimmel Cancer Center, Thomas Jefferson University
Hestia Mellert, Department of Cancer Biology, Thomas Jefferson University; Kimmel Cancer Center, Thomas Jefferson University; Biomedical Graduate Studies, University of Pennsylvania; Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder
Sankar Addya, Kimmel Cancer Center, Department of Cancer Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Adam Ertel, Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PAFollow
Ruth Birbe, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson UniversityFollow
Paolo Fortina, Kimmel Cancer Center, Thomas Jefferson University; Cancer Genomics, Thomas Jefferson UniversityFollow
Adam Dicker MD, PhD, Department of Radiation Oncology, Thomas Jefferson University; Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Karen E Knudsen, Department of Cancer Biology, Thomas Jefferson UniversityFollow
Robert Den MD, Department of Radiation Oncology, Thomas Jefferson University; Department of Cancer Biology, Thomas Jefferson University; Kimmel Cancer Center, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

11-1-2014

Comments

This article has been peer reviewed. It was published in: Clinical Cancer Research.

Volume 20, Issue 21, 1 November 2014, Pages 5468-5482.

The published version is available at DOI: 10.1158/1078-0432.CCR-14-0326

Copyright © 2014 AACR

Abstract

PURPOSE: 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 DESIGN: 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.

RESULTS: 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).

CONCLUSIONS: 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.