The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness.

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.

DOI: 10.1158/1078-0432.CCR-14-0326

Cite this paper

@article{Thangavel2014TheRT, title={The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness.}, author={Chellappagounder Thangavel and Ettickan Boopathi and Steve Ciment and Yi Liu and Raymond O'Neill and Ankur Sharma and Stephen B. McMahon and Hestia S. Mellert and Sankar Addya and Adam Ertel and Ruth C. Birbe and Paolo M Fortina and A. Dicker and Karen E. Knudsen and Robert Benjamin Den}, journal={Clinical cancer research : an official journal of the American Association for Cancer Research}, year={2014}, volume={20 21}, pages={5468-5482} }