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HORMONES AND SIGNALING

Precursor peptide progastrin_1-80 reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP

Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston, Texas 77555-1043

Submitted 9 May 2003 ; accepted in final form 17 July 2003

We recently reported that downregulation of gastrin gene expression in colon cancer cells significantly suppresses relative levels of mitochondrial cytochrome c (cyt c) oxidase Vb (Cox Vb) RNA and protein. These unexpected findings suggested the possibility that gastrin gene products [mainly progastrin (PG)] may be directly or indirectly mediating the observed effects in colon cancer cells. Because colon cancer cells do not respond to exogenous PG, we examined the possibility of whether PG regulates Cox Vb expression in gastrin-responsive intestinal epithelial cells (IECs) in vitro. Levels of Cox Vb RNA and protein were significantly increased in a dose-dependent manner in response to PG. Mitochondrial synthesis of ATP was also increased by approximately three- to fivefold in response to optimal concentrations (0.1-1.0 nm) of PG. Possible antiapoptotic effects of PG were additionally examined, because activation of caspases 9 and 3 had been noted in colon cancer cells downregulated for gastrin gene expression. We measured a significant loss in the levels of cyt c in the cytosol of PG-treated vs. control IEC cells, which correlated with a significant loss in the activation of caspases 9 and 3, resulting in a significant loss in DNA fragmentation on PG treatment of the cells. Our results thus suggest the novel possibility that the precursor PG peptide exerts direct antiapoptotic effects on IECs, which may contribute to the observed growth effects of PG on these cells. Additionally, Cox Vb gene appears to be an important intracellular target of PG, resulting in an increase in ATP levels, which may also contribute to the observed increase in the growth of target cells in response to PG.

gastrins; growth; apoptosis; colon cancer cells; adenosine 5'-triphosphatase

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