Differential expression of steroid 5alpha-reductase isozymes and association with disease severity and angiogenic genes predict their biological role in prostate cancer.
The biological role of steroid 5alpha-reductase isozymes (encoded by the SRD5A1 and SRD5A2 genes) and angiogenic factors that play important roles in the pathogenesis and vascularization of prostate cancer (PC) is poorly understood. The sub-cellular expression of these isozymes and vascular endothelial growth factor (VEGF) in PC tissue microarrays (n=62) was examined using immunohistochemistry. The effect of SRD5A inhibition on the angiogenesis pathway genes in PC was also examined in prostate cell lines, LNCaP, PC3, and RWPE-1, by treating them with the SRD5A inhibitors finasteride and dutasteride, followed by western blot, quantitative PCR, and ELISA chip array techniques. In PC tissues, nuclear SRD5A1 expression was strongly associated with higher cancer Gleason scores (P=0.02), higher cancer stage (P=0.01), and higher serum prostate specific antigen (PSA) levels (P=0.01), whereas nuclear SRD5A2 expression was correlated with VEGF expression (P=0.01). Prostate tumor cell viability was significantly reduced in dutasteride-treated PC3 and RWPE-1 cells compared with finasteride-treated groups. Expression of the angiogenesis pathway genes transforming growth factor beta 1 (TGFB1), endothelin (EDN1), TGFalpha (TGFA), and VEGFR1 was upregulated in LNCaP cells, and at least 7 out of 21 genes were upregulated in PC3 cells treated with finasteride (25 muM). Our findings suggest that SRD5A1 expression predominates in advanced PC, and that inhibition of SRD5A1 and SRD5A2 together was more effective in reducing cell numbers than inhibition of SRD5A2 alone. However, these inhibitors did not show any significant difference in prostate cell angiogenic response. Interestingly, some angiogenic genes remained activated after treatment, possibly due to the duration of treatment and tumor resistance to inhibitors.
Cancer Science Institute, Department of Pathology, National University Health System, National University of Singapore, 28 Medical Drive, Singapore. kaks23@yahoo.com
Kakoli
K
Das
Pia D N
PD
Lorena
Lai Kuan
LK
Ng
Diana
D
Lim
Liang
L
Shen
Woei Yun
WY
Siow
Ming
M
Teh
Juergen K V
JK
Reichardt
Manuel
M
Salto-Tellez
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D042501:Angiogenic Proteins / Q000378:metabolism*; D001378:Azasteroids / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000556:secondary; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D000068538:Dutasteride; D004797:Enzyme-Linked Immunosorbent Assay; D018120:Finasteride / Q000627:therapeutic use; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes; D008207:Lymphatic Metastasis; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D058891:5-alpha Reductase Inhibitors; C410798:AR protein, human; D042501:Angiogenic Proteins; D001378:Azasteroids; D014408:Biomarkers, Tumor; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548467:SRD5A1 protein, human; C548468:SRD5A2 protein, human; D000068538:Dutasteride