Upregulation of VEGF-C by androgen depletion: the involvement of IGF-IR-FOXO pathway.
Androgen ablation therapy is eventually followed by a more metastatic and androgen-refractory stage of prostate cancer. The detailed molecular mechanism of this gradual transition is not clearly understood. Recent reports correlate the high abundance of vascular endothelial growth factor-C (VEGF-C) to the lymph node metastasis seen in human prostate cancer (Tsurusaki et al., 1999). In this study, we report that androgen ablation in LNCaP cells augment the transcriptional upregulation of VEGF-C and the downregulation of the IGF-IR pathway, due to androgen withdrawal, is a potential mechanism for this observed VEGF-C transcription. Forkhead transcription factor FOXO-1, activated by SIRT-1, was identified as the downstream molecule within this pathway. Furthermore, the VEGF-C-induced increase of Bag-IL expression in LNCaP cells suggests that VEGF-C plays a role in the androgen-independent reactivation of the androgen receptor, resulting in androgen-refractory prostate cancer growth.
Li
Jinping
J
Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic Foundation, Rochester, MN 55905, USA.
Wang
Enfeng
E
Rinaldo
Francesca
F
Datta
Kaustubh
K
D000728:Androgens / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
D000728:Androgens; C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014157:Transcription Factors; D042582:Vascular Endothelial Growth Factor C; D007334:Insulin-Like Growth Factor I; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases