Carcinogenesis, Vol 18, 1375-1380, Copyright © 1997 by Oxford University Press
SA Li, DZ Liao, EM Yazlovitskaya, CG Pantazis and JJ Li
We have proposed that an early step in estrogen carcinogenesis in the
hamster kidney is tubular damage followed by reparative cell proliferation.
This tubular injury is progressive and increases in severity with continued
estrogen treatment; one pertinent feature is a marked rise in the number of
both secondary and tertiary lysosomes. Data presented herein indicate that
cathepsin D, an estrogen-responsive lysosomal proteolytic enzyme, is
increased in the kidney following estrogen treatment in the hamster. Three
isoforms of cathepsin D were detected in estrogen-treated kidneys, 52, 31,
and 27 kDa, the major being 52 kDa. At 1 and 3 months of estrogen
treatment, 52-kDa cathepsin D content increased 1.4- to 1.6-fold. These
changes coincided with a rise in renal estrogen receptor levels during the
same estrogen treatment periods. More pronounced rises in cathepsin D
levels, 2.7- and 3.5-fold, were seen after 4 and 5 months of estrogen
treatment, respectively. A concomitant, 3.0- to 4.0-fold rise in estrogen
receptor content was also observed. At 5 months of estradiol or DES
treatment, both 27- and 31-kDa isoforms were present in hamster kidneys, in
addition to the 52-kDa form. Neither progesterone nor DHT treatment
affected the untreated levels of cathepsin D. Interestingly, either
concomitant tamoxifen or DHT and estrogen treatment prevented the rise in
cathepsin D and estrogen receptor content observed after estrogen treatment
alone. Primary estrogen-induced renal tumors and their metastases exhibited
markedly elevated levels of all three isoforms of cathepsin D.
Immunohistochemical analysis of cathepsin D in kidney sections confirmed
the Western blot findings. These data suggest a novel role for
estrogen-induced cathepsin D in the hamster kidney during tumorigenesis;
that is, mediating renal tubular damage as a prelude to reparative cell
proliferation, thus initiating a multi-step estrogen-driven process which
leads to renal tumor formation.
ARTICLES
Induction of cathepsin D protein during estrogen carcinogenesis: possible role in estrogen-mediated kidney tubular cell damage
Kansas Cancer Institute, Department of Pharmacology, University of Kansas Medical Center, Kansas City 66160-7312, USA.
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