Autocrine gastrins in colon cancer cells up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3

H. Wu, G. N. Rao, B. Dai, Pomila Singh

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)32491-32498
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number42
StatePublished - Oct 20 2000

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Gastrins
Electron Transport Complex IV
Cytochromes c
Caspase 3
Colonic Neoplasms
Mitochondria
Up-Regulation
Down-Regulation
Chemical activation
Cells
Oxidoreductases
Genes
RNA
Digitonin
Camptothecin
Growth
Caspase 9
Antisense RNA
Cell Survival
Clone Cells

ASJC Scopus subject areas

  • Biochemistry

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Autocrine gastrins in colon cancer cells up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3. / Wu, H.; Rao, G. N.; Dai, B.; Singh, Pomila.

In: Journal of Biological Chemistry, Vol. 275, No. 42, 20.10.2000, p. 32491-32498.

Research output: Contribution to journalArticle

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