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

Abstract

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.

The interaction between androgen receptor and PDGF-D in the radiation response of prostate carcinoma

“…We have previously shown that PDGF D expression results in increased tumor growth and an invasive phenotype of PCa cells. Additionally, we have demonstrated that PTEN À/À murine prostate epithelial cells are radioresistant compared with PTEN þ/þ counterparts in a PDGF D-dependent manner [13]. In the present study, we demonstrate that AR is a downstream mediator of PDGF D signaling in response to irradiation in both murine and human PCa cells.…”

“…Our previous findings demonstrated a role for PDGF D in radiation resistance of murine PCa cells . We next sought to assess this phenomenon in our human PCa model.…”

“…We have previously shown that PDGF D expression induces an invasive phenotype of PCa cells and promotes intraosseous tumor growth . Importantly, we have demonstrated that PTEN deletion results in increased tumorigenicity and radiation resistance that is PDGF D dependent .…”

Three‑dimensional cell culture: A powerful tool in tumor research and drug discovery (Review)

“…3D cultured breast cancer cells in Matrigel exhibit a bidirectional cross-modulation of β1-integrin and epidermal growth factor receptor signaling via the mitogen-activated protein kinase signaling pathway, but this reciprocal modulation does not occur in monolayer culture (75). These different signal pathways included transforming growth factor β family (76) and phosphatase and tensin homolog/platelet-derived growth factor signaling network (77), which are relevant with chemotherapy and radiotherapy resistance. CSC research using Matrigel has also been performed.…”

Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers

“…EGFR, RAS) and loss of tumour suppressor gene ( e.g. PTEN) 55 56 57 58 59 60 61 . These molecular alterations ultimately lead to activation of PI3-K/AKT pathway which regulates important mechanisms of cellular radioresistance.…”