Restoration of fibroblast growth factor receptor 2IIIb enhances the chemosensitivity of human prostate cancer cells

Abstract

Abstract. Fibroblast growth factor receptor 2 (FGFR2) is thought to mediate an important signaling pathway between prostate epithelial cells and stromal cells for maintenance of homeostasis in normal prostate tissue. Abnormalities of FGFR2 have been shown in advanced prostate cancer or prostate cancer cell lines, and we previously demonstrated the tumor-suppressive effects of the restoration of FGFR2IIIb in prostate cancer cells. The aim of the present study was to determine whether FGFR2IIIb plays a role in the chemosensitivity of castration-resistant prostate cancer cells. A clonal line of PC-3 cells expressing FGFR2IIIb (PC-3R2IIIb) was established by transfection with an IRESneo2-expressing vector bearing FGFR2IIIb cDNA. The effects of chemotherapeutic agents (docetaxel, cisplatin, 5-fluorouracil and zoledronic acid) on cell viability and apoptosis were examined by MTT assay and western blot analysis, respectively. Expression levels of molecules that were markers of epithelial-to-mesenchymal transition and chemosensitivity-related proteins were assessed by western blot analysis. Viability of the PC-3R2IIIb cells was significantly lower than that of the control PC-3 cells transfected with the vector alone (PC-3neo), and viability was further suppressed by treatment with chemotherapeutic agents, particularly docetaxel. Induced expression of caspase-3 was evident in the PC-3R2IIIb cells and was further enhanced by treatment with docetaxel. Expression of N-cadherin, vimentin, survivin and XIAP was lower in the PC-3R2IIIb cells than that in the PC-3neo cells. In contrast, expression of p21 was higher in the PC-3R2IIIb cells than that in the control PC-3neo cells. These data indicate that restoration of FGFR2IIIb in castration-resistant prostate cancer cells may reverse some of the epithelial-to-mesenchymal cell properties characteristic of tumor cells and induce in part mesenchymal-to-epithelial transition properties. This together with enhancement of apoptotic pathways involving caspase-3 may enhance chemosensitivity particularly to docetaxel which is widely used in the treatment of castration-resistant prostate cancer.

Enhanced chemosensitization of anoikis-resistant melanoma cells through syndecan-2 upregulation upon anchorage independency

“…This is an interesting phenomenon but was in contrast with other observations, at which serum-depletion might induce cell apoptosis or enhance chemosensitivity [ 38 – 40 ]. However, several literatures implied the growth factors or receptors promoted or involved in cell apoptosis [ 41 – 45 ].…”

Intrinsic FGFR2 and Ectopic FGFR1 Signaling in the Prostate and Prostate Cancer

“…In addition, expression of dnFGFR2 potentiates the development and progression of prostatic intraepithelial neoplasia (PIN) lesions induced by expression of ectopic FGFR1 kinase, demonstrating the cooperation between ablation of resident FGFR2 and expression of ectopic FGFR1 in promoting PCa progression (Jin et al, 2003; Wang et al, 2004). Restoration of FGFR2IIIb in human PC cells increases the sensitivity to chemotherapeutic reagents (Shoji et al, 2014) and in stromal cells derived from the DT3327 rat PCa model restores the interaction between PCa and prostate stromal cells (Feng et al, 1997).…”

Emerging Roles of Fibroblast Growth Factor 10 in Cancer

“…Whilst these studies in mouse models of prostate cancer have revealed potential novel roles for FGF10 in androgen signaling, it is important to note that elevated FGF10 has not been detected in human prostate cancer tissue ( Abate-Shen and Shen, 2007 ; Eiro et al, 2017 ) and levels of FGF10 in the normal adult prostate are extremely low, compared to those of FGF7 ( Ropiquet et al, 2000 ). Transfection of malignant prostate tumor cells with FGFR2b cDNA has been shown to reduce the growth rate of the derived tumors ( Feng et al, 1997 ) and restoration of FGFR2b expression in castration-resistant prostate cancer cells increased sensitivity to chemotherapeutic agents ( Shoji et al, 2014 ). Further investigation is therefore required to fully elucidate the complex roles of FGF10-FGFR2b signaling in prostate tumourigenesis.…”