A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

• Published in: International journal of radiation oncology, biology, physics Vol. 88; no. 1; pp. 151 - 158
• Main Authors: Christensen, Michael, MD, Najy, Abdo J., PhD, Snyder, Michael, PhD, Movilla, Lisa S., BS, Kim, Hyeong-Reh Choi, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2014
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma - radiotherapy; Animals; Apoptosis - physiology; CARCINOMAS; CELL CYCLE; Cell Cycle - physiology; Cell Line, Tumor; Cell Movement - radiation effects; Cell Survival - radiation effects; Cell Transformation, Neoplastic - pathology; GROWTH FACTORS; Hematology, Oncology and Palliative Medicine; Lymphokines - physiology; Male; MICE; Mice, Nude; Mice, SCID; Neoplasm Invasiveness; Neoplasm Proteins - deficiency; Neoplasm Proteins - physiology; Phenotype; Platelet-Derived Growth Factor - physiology; PROSTATE; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - radiotherapy; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - physiology; Radiation Tolerance - physiology; Radiology; RADIOLOGY AND NUCLEAR MEDICINE; RADIOSENSITIVITY; Receptor, Platelet-Derived Growth Factor beta; RNA; Signal Transduction - physiology; SIGNALS
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2013.10.019

Purpose Loss or mutation of the phosphate and tensin homologue (PTEN) is a common genetic abnormality in prostate cancer (PCa) and induces platelet-derived growth factor D (PDGF D) signaling. We examined the role of the PTEN/PDGF axis on radioresponse using a murine PTEN null prostate epithelial cell model. Methods and Materials PTEN wild-type (PTEN+/+ ) and PTEN knockout (PTEN−/− ) murine prostate epithelial cell lines were used to examine the relationship between the PTEN status and radiosensitivity and also to modulate the PDGF D expression levels. PTEN−/− cells were transduced with a small hairpin RNA (shRNA) lentiviral vector containing either scrambled nucleotides (SCRM) or sequences targeted to PDGF D (shPDGF D). Tumorigenesis and morphogenesis of these cell lines were evaluated in vivo via subcutaneous injection of male nude mice and in vitro using Matrigel 3-dimensional (3D) culture. Effects of irradiation on clonogenic survival, cell migration, and invasion were measured with respect to the PTEN status and the PDGF D expression level. In addition, apoptosis and cell cycle redistribution were examined as potential mechanisms for differences seen. Results PTEN−/− cells were highly tumorigenic in animals and effectively formed foci in 3D culture. Importantly, loss of PDGF D in these cell lines drastically diminished these phenotypes. Furthermore, PTEN−/− cells demonstrated increased clonogenic survival in vitro compared to PTEN+/+ , and attenuation of PDGF D significantly reversed this radioresistant phenotype. PTEN−/− cells displayed greater migratory and invasive potential at baseline as well as after irradiation. Both the basal and radiation-induced migratory and invasive phenotypes in PTEN−/− cells required PDGF D expression. Interestingly, these differences were independent of apoptosis and cell cycle redistribution, as they showed no significant difference. Conclusions We propose that PDGF D represents a potentially promising target for PCa treatment resistance in the absence of PTEN function, and warrants further laboratory evaluation and clinical study.