Phospholipase D Prevents Etoposide-Induced Apoptosis by Inhibiting the Expression of Early Growth Response-1 and Phosphatase and Tensin Homologue Deleted on Chromosome 10

Abstract

Phospholipase D (PLD) has emerged as a critical regulator of cell proliferation and survival signaling. We show for the first time that elevated expression of PLD isozymes attenuates expression of the tumor suppressors early growth response-1 (Egr-1) and the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor and apoptosis during etoposide treatment. When formation of phosphatidic acid was inhibited by overexpression of catalytically inactive PLD during etoposide treatment, expression of Egr-1 and PTEN and the apoptotic effect of etoposide were not inhibited. This suggests that PLD inhibits expression of these tumor suppressors and inhibits apoptosis. Deletion of a specific Egr-1-binding site present in the PTEN promoter blocked etoposide-induced PTEN activity and elevated expression of PLD decreased the sensitivity to apoptosis induced by ectopic expression of Egr-1. Etoposide-induced activation of Akt was potentiated by overexpression of PLD and PLD-stimulated suppression of Egr-1 was blocked by inhibition of phosphatidylinositol 3-kinase/Akt survival pathway at the both transcriptional and posttranscriptional levels. These results show that survival signals generated by PLD attenuate expression of Egr-1 by activation of phosphatidylinositol 3-kinase signaling pathway and induction of PTEN by Egr-1, which confers resistance to apoptosis. (Cancer Res 2006; 66(2): 784-93)

Angiogenic Factor Thymidine Phosphorylase Increases Cancer Cell Invasion Activity in Patients with Gastric Adenocarcinoma

“…Phospholipase D activates p70 S6K , an observation that may be explained by the phosphatidic acid -mediated activation of mTOR (36,37). Some evidence suggests that phospholipase D activates the PI3K signaling pathway (38). Our experiments revealed Akt activation by rhTP and D-dRib, and TP-overexpressing cells displayed increased Akt activity, consistent with the findings of previous reports (39).…”

Plitidepsin Has a Dual Effect Inhibiting Cell Cycle and Inducing Apoptosis via Rac1/c-Jun NH2-Terminal Kinase Activation in Human Melanoma Cells

“…It is remarkable that AKT activation in response to other anticancer drugs has also been described. Thus, in NIH 3T3 cells doxorubicin, etoposide, and staurosporine activate AKT preceding the onset of apoptosis (Tang et al, 2001;Kim et al, 2006;Lee et al, 2006). Moreover, activation of AKT by daunorubicin has been observed in human acute myeloid leukemia cell lines (Plo et al, 1999).…”

Phorbol Ester Up-regulates Phospholipase D1 but Not Phospholipase D2 Expression through a PKC/Ras/ERK/NFκB-dependent Pathway and Enhances Matrix Metalloproteinase-9 Secretion in Colon Cancer Cells

“…Mutation in the Ras oncogene is found in many human cancers (6) and can lead to the deregulated activation of PLD and important downstream signaling pathways, including Raf/MEK/ERK (7) and PI3K/Akt (8). Moreover, PLD has been shown to be involved in the resistance of cancer cells to chemotherapeutic drugs (9,10). Despite gathering evidence regarding the regulation of PLD activity in cell function, little isknown about the functional role and regulatory mechanisms of PLD expression.…”