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J. Biol. Chem., Vol. 275, Issue 42, 32491-32498, October 20, 2000
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From the Department of Anatomy and Neurosciences, University of
Texas Medical Branch, Galveston, Texas 77555-1043
Suppression of the gastrin gene in human colon
cancer cells by stably expressing antisense (AS) gastrin RNA results in
significant growth suppression of AS cells. To understand mechanisms
mediating the growth effects of autocrine gastrins, differential
expression of transcripts by AS and control (C) clones of a
representative cell line (HCT-116) was analyzed to identify target
genes of autocrine gastrins. Six differentially expressed transcripts
were confirmed and sequenced. Of these, the RNA and protein levels of
cytochrome c oxidase (COX) Vb were significantly higher in
C versus AS cells. The expression of COX Vb by colon cancer
cells was proportional to the expression of gastrin. Higher levels of
COX Vb coprecipitated with cytochrome c in the mitochondria
of C versus AS cells. Treatment of mitochondria with
digitonin resulted in a 2-fold higher release of cytochrome
c from AS versus C mitochondria. As a
corollary, the cytosolic levels of cytochrome c were
significantly higher in AS versus C cells, which correlated
with ~2- and ~3-fold higher activation of caspase-9 and -3, respectively, in AS versus C cells in response to
camptothecin. Thus, autocrine gastrins may support growth/survival of
cells by up-regulating COX Vb, which may decrease the sensitivity of
the cancer cells to apoptotic stimuli by increasing retention of
cytochrome c in mitochondria.
Autocrine Gastrins in Colon Cancer Cells Up-regulate Cytochrome
c Oxidase Vb and Down-regulate Efflux of Cytochrome
c and Activation of Caspase-3*
*
This work was supported by National Institutes of Health
Grants CA72992 and CA60087 (to P. S.). Preliminary accounts of this work have been published in abstract form (Wu, H., Dai, B., and Singh,
P. (May 16-19) Proceedings of the Digestive Diseases Week, Orlando, FL, 1999, p. 801, Abstr. 4411; Wu, H.,
Rao, G. N., Dai, B., and Singh, P. (2000)
Gastroenterology 118, Suppl. 1, 2435).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Anatomy and
Neurosciences, University of Texas Medical Branch, 301 University Blvd., Rte. 1043, Galveston, TX 77555-1043. Tel.: 409-772-4842; Fax:
409-772-1861; E-mail: posingh@utmb.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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