Alternative phospholipase D/mTOR survival signal in human breast cancer cells

Chen, Yuhong; Rodrik, Vanessa; Foster, David A.

doi:10.1038/sj.onc.1208099

Cited by 105 publications

(137 citation statements)

References 52 publications

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“…A potential complication in the use of rapamycin in anti-cancer therapies is that in many cases, the effect of rapamycin is cytostatic and does not kill cancer cells (Neshat et al, 2001;Podsypanina et al, 2001;Law et al, 2002). We reported previously that under conditions of serum withdrawal, rapamycin induces apoptosis in MDA-MB-231 breast cancer cells (Chen et al, 2005). Consistent with the previous studies, we find that in the presence of serum growth factors, rapamycin induces G 1 arrest, rather than apoptosis.…”

Section: Discussionsupporting

confidence: 90%

“…We used the 18-h time point because cells undergoing apoptosis are harvested better at 18 than 24 h. If we treat with rapamycin for 24 h, we too observe a better accumulation in G 1 (data not shown). In the absence of serum, rapamycin treatment resulted in virtually all of the cells containing subgenomic levels of DNA-consistent with the previously reported rapamycin-induced apoptosis observed in these cells when deprived of serum (Chen et al, 2005). Thus, while rapamycin induces apoptosis in the absence of serum, in the presence of serum, rapamycin blocks cell cycle progression in G 1 .…”

Section: Tgf-b Suppresses Rapamycin-induced Apoptosis In Mda-mb-231 Csupporting

confidence: 89%

“…We therefore examined the effect of TGF-b, which can suppress cell cycle progression (Law et al, 2002;Siegel and Massague, 2003) on the ability of rapamycin to induce apoptosis in serum-starved MDA-MB-231 cells. As demonstrated previously (Chen et al, 2005) and indicated in Figure 1a, there is a large loss in cell viability in MDA-MB-231 cells subjected to serum withdrawal in the presence of rapamycin (Figure 1b). The loss in cell viability was accompanied by an increase in the cleavage of the caspase-3 substrate poly-ADPribose polymerase (PARP; Figure 1b), indicating that the cell death was due to apoptosis.…”

Section: Tgf-b Suppresses Rapamycin-induced Apoptosis In Mda-mb-231 Csupporting

confidence: 82%

“…Rapamycin treatment of MDA-MB-231 cells resulted in apoptosis in the absence of serum, but not in the presence of serum (Chen et al, 2005). These data indicated that a factor(s) in serum was suppressing rapamycin-induced apoptosis.…”

Section: Introductionmentioning

confidence: 77%

“…MDA-MB-231 human breast cancer cells have a survival signal generated by PLD that is dependent on mTOR (Hanahan and Weinberg, 2000;Zhong et al, 2003;Chen et al, 2005;Foster, 2007). Rapamycin treatment of MDA-MB-231 cells resulted in apoptosis in the absence of serum, but not in the presence of serum (Chen et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Defective TGF-β signaling sensitizes human cancer cells to rapamycin

et al. 2007

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Section: Discussionsupporting

confidence: 90%

Section: Tgf-b Suppresses Rapamycin-induced Apoptosis In Mda-mb-231 Csupporting

confidence: 89%

Section: Tgf-b Suppresses Rapamycin-induced Apoptosis In Mda-mb-231 Csupporting

confidence: 82%

Section: Introductionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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Defective TGF-β signaling sensitizes human cancer cells to rapamycin

et al. 2007

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Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Castellví

García

Rojo

et al. 2006

Cancer

161

114

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BACKGROUND.Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream.METHODS.One hundred twenty‐nine ovarian epithelial tumors were studied, including 20 serous cystadenomas, 7 mucinous cystadenomas, 11 serous borderline tumors, 16 mucinous borderline tumors, 29 serous carcinomas, 16 endometrioid carcinomas, 15 clear cell carcinomas, and 15 mucinous carcinomas. Tissue microarrays were constructed, and immunohistochemistry for the receptors epidermal growth factor receptor (EGFR) and c‐erb‐B2 was performed and with phosphorylated antibodies for protein kinase B (AKT), 4EBP1, p70S6K, S6, and ERK.RESULTS.Among 129 ovarian neoplasms, 17.8% were positive for c‐erb‐B2, 9.3% were positive for EGFR, 47.3% were positive for phosphorylated AKT (p‐AKT), 58.9% were positive for p‐ERK, 41.1% were positive for p‐4EBP1, 26.4% were positive for p70S6K, and 15.5% were positive for p‐S6. Although EGFR, p‐AKT, and p‐ERK expression did not differ between benign, borderline, or malignant tumors, c‐erb‐B2, p‐4EBP1, p‐p70S6K, and p‐S6 were expressed significantly more often in malignant tumors. Only p‐4EBP1 expression demonstrated prognostic significance (P = .005), and only surgical stage and p‐4EBP1 expression had statistical significance in the multivariate analysis.CONCLUSIONS.In patients with ovarian carcinoma, significant expression of p‐4EBP1 was associated with high‐grade tumors and a poor prognosis, regardless other oncogenic alterations upstream. This finding supports the study of this factor as a hallmark or pivotal factor in cell signaling in ovarian carcinoma that may crucial in the transmission of the proliferation cell signal and may reflect the real oncogenic role of this pathway in ovarian tumors. Cancer 2006. © 2006 American Cancer Society.

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Role of phospholipase D2 in anti‐apoptotic signaling through increased expressions of Bcl‐2 and Bcl‐xL

Lee

Choi

et al. 2007

J of Cellular Biochemistry

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We have previously reported that Fas-resistant A20 cells (FasR) have phospholipase D (PLD) activity upregulated by endogenous PLD2 overexpression. In the present study, we investigated how overexpressed PLD2 in FasR could generate survival signals by regulating the protein levels of anti-apoptotic Bcl-2 and Bcl-xL. To confirm the effect of PLD2 on Bcl-2 protein levels, we transfected PLD2 into wild-type murine B lymphoma A20 cells. The transfected cells showed markedly the increases in Bcl-2 and Bcl-xL protein levels, and became resistant to Fas-induced apoptosis, similar to FasR. Treatment of wild-type A20 cells with phosphatidic acid (PA), the metabolic end product of PLD2 derived from phosphatidylcholin, markedly increased levels of anti-apoptotic Bcl-2 and Bcl-xL proteins. Moreover, PA-induced expressions of Bcl-2 and Bcl-xL were enhanced by propranolol, an inhibitor of PA phospholydrolase (PAP), whereas completely blocked by mepacrine, an inhibitor of phospholipase A(2) (PLA(2)), suggesting that PLA(2) metabolite of PA is responsible for the increases in Bcl-2 and Bcl-xL protein levels. We further confirmed the involvement of arachidonic acid (AA) in PA-induced survival signals by showing that 1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA), PA without AA, was unable to increase Bcl-2 and Bcl-xL proteins. Moreover, PA notably increased cyclooxygenase (COX)-2 protein expression, and PA-induced expression of both Bcl-2 and Bcl-xL was inhibited by NS-398, a specific inhibitor of COX-2. Taken together, these findings demonstrate that PA generated by PLD2 plays an important role in cell survival during Fas-mediated apoptosis through the increased Bcl-2 and Bcl-xL protein levels which resulted from PLA(2) and AA-COX2 pathway.

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Alternative phospholipase D/mTOR survival signal in human breast cancer cells

Cited by 105 publications

References 52 publications

Defective TGF-β signaling sensitizes human cancer cells to rapamycin

Defective TGF-β signaling sensitizes human cancer cells to rapamycin

Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Role of phospholipase D2 in anti‐apoptotic signaling through increased expressions of Bcl‐2 and Bcl‐xL

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