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

Abstract

. LPA protects intestinal epithelial cells from apoptosis by inhibiting the mitochondrial pathway. Am J Physiol Gastrointest Liver Physiol 284: G821-G829, 2003; 10.1152/ajpgi.00406.2002.-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

Lysophosphatidic acid prevents apoptosis of Caco-2 colon cancer cells via activation of mitogen-activated protein kinase and phosphorylation of Bad

“…In human T lymphoblastoma cells, Bax expression was suppressed in response to LPA with no effect on Bcl-2 or Bad [57]. We observed a decrease in Bcl-2 in etoposide-treated Caco-2 cells, consistent with earlier studies [28,55,56]. This decrease in the expression of Bcl-2 was blocked by inhibition of the MEK/Erk pathway.…”

“…Other Bcl-2 relatives, such as Bax, Bak, and Bad, bind to Bcl-2 to promote rather than antagonize apoptosis. LPA rescued normal rat intestinal IEC-6 cells from camptothecin-induced apoptosis by inactivation of caspase 9 and 3 and upregulation of Bcl-2 expression [55]. In confluent Caco-2 cell cultures, inhibition of the MEK/Erk pathway induced apoptosis with a significant decrease in the expression of Bcl-2 and Bcl-X L , whereas a decrease in Bcl-2 but not Bcl-X L was observed in subconfluent Caco-2 or human intestinal crypt cells [28,56].…”

Lysophosphatidic Acid Decreases the Nuclear Localization and Cellular Abundance of the p53 Tumor Suppressor in A549 Lung Carcinoma Cells

“…6). The PI3K/Akt signaling pathway is important for cell survival of normal and tumorigenic cells (3,28,66,67). Downstream of PI3K, Akt phosphorylates the E3 ubiquitin ligase MDM2, which enhances both MDM2's nuclear import and its ubiquitin ligase activity.…”

“…Lysophosphatidic acid (LPA) is a bioactive lipid found in body fluids that influences a wide range of processes, including cell proliferation, migration, morphologic changes, survival, and neointimal formation (1)(2)(3)(4)(5)(6)(7). LPA is produced in blood by activated platelets to facilitate wound healing (8,9) and it is also produced by a variety of cancer cells (10,11).…”

“…The levels of LPA are high in ascites fluid and plasma of patients with ovarian tumors (23). LPA protects against apoptosis caused by chemotherapeutic agents (3). It promotes ovarian tumor development, possibly involving increased cyclin D expression (24).…”