Abstract |
Although initially reported as an androgen-repressed gene in the rat prostate, the functional role of testosterone-repressed prostate message-2 (TRPM-2) in apoptosis remains undefined. Inhibition of castration-induced apoptosis by calcium channel blocker treatment in androgen-dependent Shionogi tumors resulted in the prevention of TRPM-2 gene up-regulation, suggesting that TRPM-2 is not directly androgen-repressed, but is regulated by apoptotic stimuli. The overexpression of the TRPM-2 gene in human androgen-dependent LNCaP prostate cancer cells by stable transfection rendered them highly resistant to androgen ablation in vivo. We then tested the efficacy of antisense TRPM-2 oligodeoxynucleotide (ODN) therapy in the Shionogi tumor model and demonstrated that the systemic administration of antisense TRPM-2 ODNs in mice bearing Shionogi tumors after castration resulted in a more rapid onset of apoptosis and time to complete regression, as well as a significant delay of emergence of androgen-independent recurrent tumors compared to control ODN treatment. Collectively, these findings illustrate that TRPM-2 is an antiapoptotic rather than an androgen-repressed gene that confers resistance to androgen ablation and thereby helps accelerate the progression to androgen independence.
|
Authors | H Miyake, C Nelson, P S Rennie, M E Gleave |
Journal | Cancer research
(Cancer Res)
Vol. 60
Issue 1
Pg. 170-6
(Jan 01 2000)
ISSN: 0008-5472 [Print] United States |
PMID | 10646870
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- CLU protein, human
- Calcium Channel Blockers
- Clu protein, mouse
- Clusterin
- Glycoproteins
- Molecular Chaperones
- Neoplasm Proteins
- Oligodeoxyribonucleotides, Antisense
- RNA, Messenger
|
Topics |
- Animals
- Apoptosis
(drug effects)
- Blotting, Northern
- Blotting, Western
- Calcium Channel Blockers
(pharmacology)
- Clusterin
- Disease Progression
- Genetic Vectors
- Glycoproteins
(drug effects, genetics, metabolism)
- Humans
- In Situ Nick-End Labeling
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Molecular Chaperones
- Neoplasm Proteins
(drug effects, genetics, metabolism)
- Neoplasms, Hormone-Dependent
(metabolism)
- Oligodeoxyribonucleotides, Antisense
- Orchiectomy
- Prostatic Neoplasms
(metabolism)
- RNA, Messenger
(metabolism)
- Up-Regulation
(drug effects)
|