Control of tumor progression by maintenance of apoptosis.
The ability to induce multiple apoptotic regressions of an androgen-dependent tumor cell population by repeated cycles of androgen withdrawal and replacement may be advantageous in therapeutic strategies aimed at delaying or preventing tumor progression. With greater insight into factors that either initiate or limit apoptosis, more efficient application of intermittent therapy might be achieved, especially if methods could be devised to increase the length or number of treatment cycles. Both calreticulin and clusterin represent proteins with a potential role in the regulation of apoptosis. Calreticulin may inhibit target gene transcription by interacting with steroid hormone receptors, thereby masking their DNA-binding sites and triggering the onset of the apoptotic process. Clusterin, on the other hand, is a membrane-stabilizing protein that appears to be involved in limiting the autophagic lysis of epithelial cells during apoptosis. Also, the increasing tendency for nuclear localization of clusterin after androgen withdrawal may preserve the nuclear environment, limiting the lethal effect of treatment. Thus, tumor progression, characterized by the loss of apoptotic potential, appears to be linked in part to the inappropriate activation of TRPM-2 gene, which accounts for the constitutive expression of clusterin.
Bruchovsky
N
N
Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, British Columbia, Canada.
Snoek
R
R
Rennie
P S
PS
Akakura
K
K
Goldenberg
L S
LS
Gleave
M
M
D000595:Amino Acid Sequence; D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000627:therapeutic use; D037282:Calreticulin; D051152:Clusterin; D006023:Glycoproteins / Q000627:therapeutic use; D006801:Humans; D008297:Male; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D012261:Ribonucleoproteins / Q000627:therapeutic use
D000726:Androgen Antagonists; C495242:CLU protein, human; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D012261:Ribonucleoproteins