Triiodothyronine modulates cell proliferation of human prostatic carcinoma cells by downregulation of the B-cell translocation gene 2.
BACKGROUND
Studies suggest that triiodothyronine (T3) and cognate nuclear receptors (hTR) are involved in regulation of prostatic cell growth and differentiation. To probe mechanisms for T3 effects, we studied prostate carcinoma cells, investigating the effect of T3 on expression of the B-cell translocation gene 2 (BTG2), which regulates the G1/S transition of the cell cycle.


METHODS
Effects of T3 on cell proliferation were determined by (3)H-thymidine incorporation. T3 modulation of BTG2 expression was investigated using immunoblots, Northern blots, and transient gene expression assays. The putative T3 response element was determined by electrophoretic mobility shift assay.


RESULTS
T3 (0.1-1,000 nM) enhanced threefold the proliferation of prostate carcinoma cells and human androgen-dependent prostate carcinoma cells (LNCaP), but not PC-3 cells. T3 also inhibited BTG2 gene expression in LNCaP cells. Reporter assays showed that T3 downregulates by 50% promoter activity of the BTG2 gene in LNCaP cells but not PC-3 cells or thyroid-hormone receptor (TRbeta1)-overexpression PC-3 cells. Deleting the putative thyroid hormone response element (TRE; AGCGATGACCTCAGCG) blocked the inhibitory effect of T3 on BTG2 promoter activity. Electrophoretic mobility shift assays with purified TRbeta1 from in vitro translation, or with nuclear extracts from LNCaP cells and PC-3 cells, demonstrated the presence of T3 receptor binding sites in the TRE region.


CONCLUSIONS
These results suggested that the T3 upregulates proliferation of LNCaP cells by downregulating BTG2 gene expression through the consensus TRE pathway.
Tsui
Ke-Hung
KH
Department of Urology, Chang Gung Memorial Hospital, Kwei-Shan, Tao-Yuan, Taiwan, ROC.
Hsieh
Wen-Chi
WC
Lin
Mei-Hsien
MH
Chang
Phei-Lang
PL
Juang
Horng-Heng
HH
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D011988:Receptors, Thyroid Hormone; C051065:THRSP protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014284:Triiodothyronine; C070114:BTG2 protein, human