Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis

Deng, Wen; Balázs, Louisa; Wang, De-An; Middlesworth, L. Van; Tigyi, Gábor; Johnson, Leonard R.

doi:10.1053/gast.2002.34209

Cited by 113 publications

(137 citation statements)

References 43 publications

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“…Therefore, we investigated the ability of S. enterica serovar Typhimurium to protect cells against the activity of camptothecin (CPT), a topoisomerase inhibitor that induces apoptosis in a caspase-3-dependent manner (40,41). For these experiments bacteria were internalized into HeLa cells for 10 min, extracellular bacteria were then removed by washing, CPT was added, and the cells incubated for a further 3 h. The cytokeratin 18 cleavage assay was then used to detect apoptotic cells.…”

Section: Epithelial Cells Infected With the ⌬Sopb Mutant Have Increasmentioning

confidence: 99%

The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt

Knodler

Finlay

Steele‐Mortimer

2005

Journal of Biological Chemistry

213

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Invasion of epithelial cells by Salmonella enterica is mediated by bacterial "effector" proteins that are delivered into the host cell by a type III secretion system. Although primarily known for their roles in actin rearrangements and membrane ruffling, translocated effectors also affect host cell processes that are not directly associated with invasion. Here, we show that SopB/SigD, an effector with phosphoinositide phosphatase activity, has anti-apoptotic activity in Salmonellainfected epithelial cells. Salmonella induced the sustained activation of Akt/protein kinase B, a pro-survival kinase, in a SopB-dependent manner. Failure to activate Akt resulted in increased levels of apoptosis after infection with a sopB deletion mutant (⌬sopB). Furthermore, cells infected with wild type bacteria, but not the ⌬sopB strain, were protected from camptothecin-induced cleavage of caspase-3 and subsequent apoptosis. The anti-apoptotic activity of SopB was dependent on its phosphatase activity, because a catalytically inactive mutant was unable to protect cells from the effects of camptothecin. Finally, small interfering RNA was used to demonstrate the essential role of Akt in SopB-mediated protection against apoptosis. These results provide new insights into the mechanisms of apoptosis and highlight how bacterial effectors can intercept signaling pathways to manipulate host responses.

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Section: Epithelial Cells Infected With the ⌬Sopb Mutant Have Increasmentioning

confidence: 99%

The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt

Knodler

Finlay

Steele‐Mortimer

2005

Journal of Biological Chemistry

213

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“…To investigate the physiologic significance of LPA-induced reduction of p53, we examined the effects of LPA on actinomycin D -induced cell death in A549 cells. LPA protects both ovarian cancer cells and normal intestinal epithelial cells from apoptosis induced by chemotherapeutic agents (54,55). A549 cells were incubated with or without 10 Amol/L LPA in the presence or absence of 2 Ag/mL actinomycin D 24 h before determining cell viability (Fig.…”

Section: Lpa Partially Protects A549 Cells From Genotoxic Stressinducmentioning

confidence: 99%

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

Murph

Hurst-Kennedy

Newton

et al. 2007

Molecular Cancer Research

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Lysophosphatidic acid (LPA) is a bioactive lipid that promotes cancer cell proliferation and motility through activation of cell surface G protein -coupled receptors. Here, we provide the first evidence that LPA reduces the cellular abundance of the tumor suppressor p53 in A549 lung carcinoma cells, which express endogenous LPA receptors. The LPA effect depends on increased proteasomal degradation of p53 and it results in a corresponding decrease in p53-mediated transcription. Inhibition of phosphatidylinositol 3-kinase protected cells from the LPA-induced reduction of p53, which implicates this signaling pathway in the mechanism of LPA-induced loss of p53. LPA partially protected A549 cells from actinomycin D induction of both apoptosis and increased p53 abundance. Expression of LPA 1 , LPA 2 , and LPA 3 receptors in HepG2 hepatoma cells, which normally do not respond to LPA, also decreased p53 expression and p53-dependent transcription. In contrast, neither inactive LPA 1 (R124A) nor another G i -coupled receptor, the M 2 muscarinic acetylcholine receptor, reduced p53-dependent transcription in HepG2 cells. These results identify p53 as a target of LPA action and provide a new dimension for understanding how LPA stimulates cancer cell division, protects against apoptosis, and thereby promotes tumor progression.

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“…For example, activation of LPA 1 prevented apoptosis in primary lymphocytic leukemia cells, whereas the same LPA 1 induced apoptosis and anoikis in ovarian cancer cells [14,15]. In untransformed rat intestinal epithelial IEC-6 cells, both LPA 1 and LPA 2 are thought to be responsible for the anti-apoptotic effect of LPA [16], but the effect in colon cancer cells is not known.…”

Section: Introductionmentioning

confidence: 99%

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

Rusovici

Ghaleb

Shim

et al. 2007

Biochimica et Biophysica Acta (BBA) - General Subjects

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Lysophosphatidic acids (LPA) exert growth factor-like effects through specific G protein-coupled receptors. The presence of different LPA receptors often determines the specific signaling mechanisms and the physiological consequences of LPA in different environments. Among the four members of the LPA receptor family, LPA 2 has been shown to be overexpressed in colon cancer suggesting that the signaling by LPA 2 may potentiate growth and survival of tumor cells. In this study, we examined the effect of LPA on survival of colon cancer cells using Caco-2 cells as a cell model system. LPA rescued Caco-2 cells from apoptosis elicited by the chemotherapeutic drug, etoposide. This protection was accompanied by abrogation of etoposide-induced stimulation of caspase activity via a mechanism dependent on Erk and PI3K. In contrast, perturbation of cellular signaling mediated by the LPA 2 receptor by knockdown of a scaffold protein NHERF2 abrogated the protective effect of LPA. Etoposide decreased the expression of Bcl-2, which was reversed by LPA. Etoposide decreased the phosphorylation level of the proapoptotic protein Bad in an Erkdependent manner, without changing Bad expression. We further show that LPA treatment resulted in delayed activation of Erk. These results indicate that LPA protects Caco-2 cells from apoptotic insult by a mechanism involving Erk, Bad, and Bcl-2.

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Lysophosphatidic acid protects and rescues intestinal epithelial cells from radiation- and chemotherapy-induced apoptosis

Cited by 113 publications

References 43 publications

The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt

The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt

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

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

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