Restoration of fibroblast growth factor receptor 2IIIb enhances the chemosensitivity of human prostate cancer cells.
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.
Department of Urology, Institute of Biomedical and Health Sciences, Integrated Health Science, Hiroshima University, Hiroshima 734-8551, Japan.
Koichi
K
Shoji
Department of Urology, Institute of Biomedical and Health Sciences, Integrated Health Science, Hiroshima University, Hiroshima 734-8551, Japan.
Jun
J
Teishima
Department of Urology, Institute of Biomedical and Health Sciences, Integrated Health Science, Hiroshima University, Hiroshima 734-8551, Japan.
Tetsutaro
T
Hayashi
Department of Urology, Institute of Biomedical and Health Sciences, Integrated Health Science, Hiroshima University, Hiroshima 734-8551, Japan.
Shinya
S
Ohara
Center for Cancer and Stem Cell Biology, Institute of Bioscience and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
Wallace L
WL
Mckeehan
Department of Urology, Institute of Biomedical and Health Sciences, Integrated Health Science, Hiroshima University, Hiroshima 734-8551, Japan.
Akio
A
Matsubara
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D000970:Antineoplastic Agents; D020033:Protein Isoforms; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D053148:Caspase 3