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Am J Physiol Gastrointest Liver Physiol 284: G821-G829, 2003; doi:10.1152/ajpgi.00406.2002
0193-1857/03 $5.00
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Vol. 284, Issue 5, G821-G829, May 2003

LPA protects intestinal epithelial cells from apoptosis by inhibiting the mitochondrial pathway

Wenlin Deng, De-An Wang, Elvira Gosmanova, Leonard R. Johnson, and Gabor Tigyi

Department of Physiology, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163

We previously showed (Gastroenterology 123: 206-216, 2002) that lysophosphatidic acid (LPA) protects and rescues rat intestinal epithelial cells (IEC-6) from apoptosis. Here, we provide evidence for the LPA-elicited inhibition of the mitochondrial apoptotic pathway leading to attenuation of caspase-3 activation. Pretreatment of IEC-6 cells with LPA inhibited campothecin-induced caspase-9 and caspase-3 activation and DNA fragmentation. A caspase-9 inhibitor peptide mimicked the LPA-elicited antiapoptotic activity. LPA elicited ERK1/ERK2 and PKB/Akt phosphorylation. The LPA-elicited antiapoptotic activity and inhibition of caspase-9 activity were abrogated by pertussis toxin, PD 98059, wortmannin, and LY 294002. LPA reduced cytochrome c release from mitochondria and prevented activation of caspase-9. LPA prevented translocation of Bax from cytosol to mitochondria and increased the expression of the antiapoptotic Bcl-2 mRNA and protein. LPA had no effect on Bcl-xl, Bad, and Bak mRNA or protein expression. These data indicate that LPA protects IEC-6 cells from camptothecin-induced apoptosis through Gi-coupled inhibition of caspase-3 activation mediated by the attenuation of caspase-9 activation due to diminished cytochrome c release, involving upregulation of Bcl-2 protein expression and prevention of Bax translocation.

lysophosphatidic acid; camptothecin; cytochrome c; Bcl-2 protein; caspase-9; caspase-3/cpp32


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