mTOR-dependent Suppression of Protein Phosphatase 2A Is Critical for Phospholipase D Survival Signals in Human Breast Cancer Cells

Li, Hui; Rodrik, Vanessa; Pielak, Rafal M.; Knirr, Stefan; Yang, Zheng; Foster, David A.

doi:10.1074/jbc.m504192200

Cited by 51 publications

(38 citation statements)

References 44 publications

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“…Elevated PLD activity has been shown to suppress the expression of tumor suppressor p53 [31]. PLD has also been reported to inhibit the activity of another tumor suppressor -protein phosphatase 2A [32]. PLD increases the stability, and consequently the expression of Myc [33,34].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…Although survival signals generated by PLD are dependent on mTOR (Chen et al, 2005;Hui et al, 2005), the effect of PLD on p53 expression in MDA-MB-231 cells was independent of mTOR, suggesting that activation of mTOR by PLD has additional effects for the survival signals generated by PLD. The effect of PLD on p53 expression in MDA-MB-231 cells was dependent on the MAP kinase pathway.…”

Section: Survival Signals Generated By Pld Are Dependent Upon Mutant P53mentioning

confidence: 98%

“…Twenty-four hours later, the cells were shifted to fresh media containing 0% serum for 48 h, at which time the percentage of non-viable cells was determined by trypan blue exclusion as described previously (Hui et al, 2004(Hui et al, , 2005. At this time, cells were also examined for the level of cleaved PARP (Cl PARP) and PLD2 protein using Western blot analysis as described previously (Hui et al, 2004(Hui et al, , 2005. Blots were stripped and reprobed with an antibody to actin to control for loading.…”

Section: Survival Signals Generated By Pld Are Dependent Upon Mutant P53mentioning

confidence: 99%

Mutant p53 in MDA-MB-231 breast cancer cells is stabilized by elevated phospholipase D activity and contributes to survival signals generated by phospholipase D

et al. 2006

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p53 is the most commonly mutated gene in human cancer. Although the loss of tumor suppressor functions for p53 in tumorigenesis is well characterized, gain-of-function p53 mutations observed in most cancers are not as widely appreciated. The human breast cancer cell line MDA-MB-231, which has high levels of a mutant p53, has high levels of phospholipase D (PLD) activity, which provides a survival signal in these cells when deprived of serum growth factors. We report here that the mutant p53 in MDA-MB-231 cells is stabilized by the elevated PLD activity in these cells. Surprisingly, the survival of MDA-MB-231 cells deprived of serum was dependent on the mutant p53. These data indicate that a mutant p53, stabilized by elevated PLD activity, can contribute to the suppression of apoptosis in a human breast cancer cell line and suggest a rationale for the selection of p53 mutations early in tumorigenesis to suppress apoptosis in an emerging tumor.

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“…21 Prior work has shown that mTOR inhibitors, including rapamycin, lead to the desphosphorylation of Bad with subsequent apoptosis. 22 We harvested lymph node cells from CBA-lpr cg mice treated with rapamycin and from control mice to assess phosphorylation of Bad. We were able to show decreased phosphorylated Bad in rapamycin-treated mice (Figure 7), suggesting activation of the intrinsic mitochondrial pathway.…”

Section: Assessment Of Mechanism Of Response To Rapamycinmentioning

confidence: 99%

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)

Teachey

Obzut

Axsom

et al. 2006

Blood

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Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of doublenegative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r ‫؍‬ .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans. (Blood. 2006;108: 1965-1971

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mTOR-dependent Suppression of Protein Phosphatase 2A Is Critical for Phospholipase D Survival Signals in Human Breast Cancer Cells

Cited by 51 publications

References 44 publications

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

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

Mutant p53 in MDA-MB-231 breast cancer cells is stabilized by elevated phospholipase D activity and contributes to survival signals generated by phospholipase D

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)

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