bxl628 and Prostatic-Neoplasms

Suppression of invasive phenotype is essential in developing new therapeutic tools to treat prostate cancer (PC). Evidence indicates that androgen-dependent (AD) prostate cancer cells are characterized by a lower malignant phenotype. We have demonstrated that transfection with an androgen receptor (AR) expression vector of the androgen-independent (AI) prostate cancer cell line PC3 decreases invasion of these cells through modulation of alpha6beta4 integrin expression, indicating a genotropic effect of androgens in inhibiting invasion ability of AD PC cells. Later on, we have shown that also a non-genotropic mechanism is involved in such an effect. By using immunoconfocal fluorescent microscopy, we demonstrated that AR in PC3-AR cells co-localizes with the EGFR receptors (EGFR) in PC3-AR cells. Co-immunoprecipitation studies both in PC3-AR cells and in the AD cell line LNCaP that physiologically express both receptors, confirm the occurrence of an interaction between of the two proteins. In PC3-AR cells, we demonstrated a disruption of EGFR signalling properties (reduced EGF-induced EGFR autotransphosphorylation, reduced EGF-stimulated PI3K activity as well as EGFR-PI3K interaction) contributing to the lower invasive phenotype of these cells. In another study, we investigated the effects of a new Vitamin D analogue, BXL628, on invasion in response to KGF in the androgen-independent PC cell line DU145. We found that the compound was able to reduce proliferation and invasion of the cells in response to the growth factor. In addition, we found that KGF-induced autotransphosphorylation of KGF receptor (KGFR) and PI3K activation were suppressed after short-term (5min) pre-treatment with the analogue before addition of KGF. Collectively, these studies demonstrate that a non-genotropic effect due to a direct interaction of the androgen receptor with EGFR and to a rapid effect of a Vitamin D agonist on KGFR may disrupt signalling of GF leading to decreased tumorigenicity and a less malignant phenotype of PC cells in vitro.

Topics: Antineoplastic Agents; Calcitriol; Cell Line, Tumor; Genomics; Growth Inhibitors; Humans; Male; Neoplasm Invasiveness; Prostatic Neoplasms; Receptors, Androgen; Vitamin D

Suppression of the invasive phenotype is essential in developing new therapeutic tools to treat advanced prostate cancer (PC) indicating that androgen-independent prostate cancer (AI-PC) is characterized by increased metastatic potential. In the present study, we have investigated the effect of the nonhypercalcemic vitamin D analogue BXL-628 on proliferation and invasive properties of the human PC cell line DU145. In particular, the effect of the analogue was tested following stimulation with a potent growth factor, keratinocyte growth factor (KGF), which stimulates both proliferation and invasion of these cells. We have also evaluated the effect of the analogue on KGF stimulation of PI3K/AKT signaling pathway.. Cell proliferation was determined by cell counting. Invasion through Matrigel was evaluated using Boyden chambers. PI3K activity was measured by immunokinase assay and AKT phosphorylation was evaluated by western blot analysis. Keratinocyte growth factor receptor (KGFR) autotransphosphorylation was evaluated by western blot after immunoprecipitation of the receptor.. BXL-628 is able to inhibit both proliferation and invasion of DU145 cells in basal conditions and in response to KGF. Following stimulation with KGF, the inhibition is due to suppression of KGFR autotransphosphorylation and downstream PI3K/AKT activation, both achieved following a brief (5 min) incubation with the analogue. This effect on KGFR autophosphorylation was still present when cells were treated with the alpha-amanitin, an inhibitor of RNA transcription, indicating a rapid, nongenomic effect.. Our results demonstrate that the vitamin D analogue BXL-628 is able to suppress KGF-induced proliferation and invasion of AI-PC cells in vitro, prospecting a possible use of the drug, which is currently in phase II clinical studies for benign prostatic hyperplasia, in the treatment of advanced prostate cancer.

Topics: Calcitriol; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fibroblast Growth Factor 7; Humans; Male; Neoplasm Invasiveness; Prostatic Neoplasms; Signal Transduction; Tumor Cells, Cultured