ANALYSIS OF TR3 RECEPTOR IN APOPTOSIS OF PROSTATE CANCER AND APPLICATION FOR DIAGNOSIS OF PROSTATE CANCER RECCURENCE
| Project/Area Number |
08671830
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | YOKOHAMA CITY UNIVERSITY |
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Principal Investigator |
UEMURA Hiroji DEP.UROL., YOKOHAMA CITY UNIVERSITY, ASSIST.PROF, 医学部, 講師 (50244439)
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| Co-Investigator(Kenkyū-buntansha) |
HOSAKA Masahiko DEP.UROL., YOKOHAMA CITY UNIVERSITY, PROF, 医学部, 教授 (30106330)
KUBOTA Yoshinobu DEP.UROL., YOKOHAMA CITY UNIVERSITY, ASSOC.PROF, 医学部, 助教授 (10106312)
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| Project Period (FY) |
1996 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1998: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1997: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1996: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Keywords | PROSTATE CANCER / STEROID RECEPTOR / APOPTOSIS |
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| Research Abstract |
(1) A role of TR3 orphan receptor in drug-induced prostate apoptosis
In androgen-responsive LNCaP human prostatic cancer cells, human TR3 orphan receptor can be rapidly induced by stimulation of androgen or growth factors (i.e., EGF or FGF). In contrast, ablation of androgen by castration can also induce the expression of TR3 orphan receptor gene in rat ventral prostate which underwent programmed cell death (apoptosis) characterized by DNA fragmentation ladder. This phenomenon prompted us to further analyze the roles of human TR3 orphan receptor in apoptosis-induced prostate cancer cells. Northern blot analysis shows that human TR3 orphan receptor can be induced rapidly after treatment of 10 mM calcium ionophore or 300 mM etoposide (VP 16) in LNCaP cells. Antisense TR3 orphan receptor stable transfectant LNCaP cells indicated a much higher concentration of etoposide was needed to show the similar apoptosis as compared to the control (vector) stable transfectant LNCaP cells. Together, ou
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r data suggest that human TR3 orphan receptor may play an important role of drug-induced apoptosis in human prostate cancer cells.
(2) Induction of an intronic enhancer of the human ciliary neurotrophic factor receptor (CNTFR) gene by the TR3 orphan receptor
A hormone response element, CNTER-NERB (5'-AAAGGTCA-3') has been identified in the fifth intron of the alpha component of CNTFR gene for the human TR3 orphan receptor. A specific binding between in vitro expressed TR3 and CNTFR-NBRE was demonstrated by using electrophoretic mobility shift assay. A reporter gene assay using CAT showed that CNTFR has an enhancer activity that could be induced by TR3 receptor in a dose-dependent manner. This induction was significantly reduced in the absence of CNTFR-BNBRE. Together, these results indicate CNTFR-NBRE is sufficient to mediate TR3 action in inducing the enhancer activity of CNTFR. Our finding may, therefore, suggest CNTFR is a target gene regulated by TR3 and expand the role of TR3 in the nervous system.
(3) In situ hybridization of TR3 receptor in prostate cancer tissues.
Recently, Jenkins et al. showed clear data in which c-myc amplification in prostate cancer tissues and metastatic lymphnodes was detected using fluorescence in situ hybridization. Our in situ hybridization data in human prostate cancer, benign prostate hypertrophy, and normal prostate tissues revealed that the expression patterns of TR3 orphan receptor mRNA were very similar to those of c-myc. More interestingly, TR3 orphan receptor mRNAs were more highly expressed in prostate cancer area than in adjacent normal or benign hypertrophic tissue. Furthermore, these expressions were highly seen in poorly differentiated adenocarcinoma area. These data suggest that the TR3 orphan receptor may play some important roles in development or progression of prostate cancer in the same manner as the c-myc oncogene.
(4) Telomerase activities in prostate cancer tissues.
We analyzed the telomerase activity in association with the pathological differentiation of prostate cancer. Telomerase activity was examined by PCR-based telomeric repeat amplification protocol (TRAP) assay. The results showed that most of prostate cancer tissues (90%) displayed telomerase activity and high activity in primary and biopsy specimens were more frequent detected in poorly differentiated adenocarcinoma. Also, the expression of catalytic subunit, hTERT, was detected by RT-PCR. It revealed that the expression in 70% of prostate cancer tissues was more highly seen in comparison with those in normal prostate tissues. Less
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