Phospholipase D provides a survival signal in human cancer cells with activated H-Ras or K-Ras

Abstract

Phospholipase D (PLD) is elevated in rodent fibroblasts expressing activated H-Ras mutants. We therefore examined the PLD activity in human cancer cells with activating Ras mutations. T24 bladder carcinoma cells express an activated H-Ras gene and Calu-1 lung carcinoma cells express an activated K-Ras gene. We report here that both of these cancer cell lines express highly elevated levels of PLD activity and that the PLD activity is dependent upon Ras. We also show that the PLD activity is dependent upon the Ras effector molecules RalA and phosphatidylinositol-3-kinase (PI3K). PLD activity has been shown to provide a survival signal in breast cancer cell lines that suppressed stress-induced apoptosis. Suppression of PLD activity in the T24 and Calu-1 cells resulted in apoptotic cell death in the absence of serum, indicating that the elevated PLD activity provided a survival signal in these cancer cell lines. Suppression of Ras, RalA, or PI3K also led to apoptosis in the absence of serum. These data indicate that a critical component of Ras signaling in human cancer cells is the activation of PLD and that targeting PLD survival signals in cancer cells could be an effective strategy to induce apoptosis in human cancers with activating Ras mutations.

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

“…Of significance, both mTOR and Raf have been implicated in human cancer. Consistent with this emerging role for PA in regulating cell proliferation, elevated expression and/or activity of enzymes that generate PA is commonly observed in human cancer, most notably phospholipase D (PLD) (5,6), which is elevated especially in K-Ras-driven cancers (7)(8)(9). Other enzymes that generate PA (lysophosphatidic acid (LPA) acyltransferase (LPAAT), and diacylglycerol (DG) kinase (DGK) (Fig.…”

“…We previously reported that in response to serum withdrawal there was a substantial increase in PLD activity in cancer cells (7), most notably in cancer cells harboring Ras mutations (9). More recently, we reported that PLD activity is also elevated in response to changing from medium with 10% serum to 10% delipidated serum (48).…”

Differential roles for the p101 and p84 regulatory subunits of PI3Kγ in tumor growth and metastasis

“…MDA-MB-231 cells express a high level of phospholipase D (Zhong et al, 2003), which has been shown to specifically interact with PIP 3 , enhancing its anti-apoptotic activity (Ching et al, 1999). Loss of PIP 3 because of loss of PI3Kg activity would in turn lead to a loss of phospholipase D-dependent anti-apoptotic signaling (Yamada et al, 2004;Shi et al, 2007). Likewise, accumulation of active Akt also has anti-apoptotic effects by upregulating transcription factors that constitutively activate survival genes (Nicholson and Anderson, 2002;Osaki et al, 2004).…”

mTOR signaling: PLD takes center stage

“…For instance, TSC and PLD are both modulated by mitogens (e.g., serum and insulin) [40][41][42][43][44][45][46] and TNFα. 15,47 The Ras-Raf-MEK-Erk pathway inhibits TSC2 via phosphorylation by either Erk 48,49 or a downstream kinase Rsk, 50 at the same time PLD activation by Ras [51][52][53][54] or Erk 54,55 has also been suggested. Most recently, our studies have uncovered a direct interaction between Rheb and PLD1.…”