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Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer.

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.
AuthorsH Miyake, C Nelson, P S Rennie, M E Gleave
JournalCancer research (Cancer Res) Vol. 60 Issue 1 Pg. 170-6 (Jan 01 2000) ISSN: 0008-5472 [Print] United States
PMID10646870 (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)

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