NGF/γ-IFN inhibits androgen-independent prostate cancer and reverses androgen receptor function through downregulation of FGFR2 and decrease in cancer stem cells.
Androgen-independent prostate cancer (AIPC) is difficult to treat. Present study is to explore the inhibitory effect of a cytokine environment on AIPC and its mechanism. We utilized nerve growth factor (NGF)/γ-interferon (γ-IFN) to change the cytokine environment. Animal models and 2 androgen receptor (AR)-negative prostate cancer cell lines were used to evaluate the effect of NGF/γ-IFN. Flow cytometry, immunocytochemistry, western blotting, Tunel assay, colony formation efficiency, gene microarray, and in vivo bioluminescence were used to discern the mechanisms within NGF/γ-IFN that effect the environment. In vitro, NGF/γ-IFN effectively inhibited the proliferation of AIPC cell lines and promoted the apoptosis of the cancer cells. In vivo, NGF/γ-IFN suppressed the growth and metastasis of a tumor mass that arose from the AIPC cell line. After NGF/γ-IFN treatment, the AR-negative cell lines re-expressed AR and were then able to respond to the androgen. Contrary to expectations, the proliferation of cells was inhibited after dihydrotestosterone was added, and the results indicated that NGF/γ-IFN decreased the proportion of cancer stem cells. NGF/γ-IFN worked mainly through the downregulation of fibroblast growth factor receptor 2.
Department of Urology, Zhongshan Hospital of Fudan University, Shanghai, People's Republic of China.
Wei
W
Chen
Guo-Min
GM
Wang
Jian-Ming
JM
Guo
Li-An
LA
Sun
Hang
H
Wang
D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis*; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D014183:Transplantation, Heterologous; D051155:Wnt1 Protein / Q000096:biosynthesis; D051154:Wnt2 Protein / Q000096:biosynthesis
C502240:NGF protein, human; D011944:Receptors, Androgen; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051154:Wnt2 Protein; D013196:Dihydrotestosterone; D007371:Interferon-gamma; D020932:Nerve Growth Factor; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2