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

Kang, Dong Woo; Park, Mi Hee; Lee, Young Jun; Kim, Hyung Sik; Kwon, Taeg Kyu; Park, Won-Sang; Min, Do Sik

doi:10.1074/jbc.m707416200

Cited by 70 publications

(74 citation statements)

References 33 publications

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“…16 Thus, we tried to determine whether ligands that stimulate PLD activity might induce PLD expression. We confirmed that physiological ligands such as PDGF, EGF or IL-1b stimulated PLD activity in SK-BR3 breast cancer cells (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

“…16,21 Zones of gelatinolytic activity were detected as clear bands against a blue background. Inverted images are presented.…”

Section: Zymographymentioning

confidence: 99%

“…The human PLD1 (pGL4-PLD1 Luc) and PLD2 (pGL4-PLD2 Luc) promoter reporter plasmids contained 1.9 and 2.6 kb, respectively, of upstream 5 0 -flanking DNA linked to luciferase reporter genes and have been described elsewhere. 16 We have reported that PLD1 promoter contained the conserved NFjB-binding sites. 16 A site-specific mutation was introduced into the NFjB-binding sites on PLD1 promoter by Quick Change Site-Directed Mutagenesis Kit (Stratagene, LaJolla, CA).…”

Section: Plasmids and Small Interfering Rnamentioning

confidence: 99%

“…16 We have reported that PLD1 promoter contained the conserved NFjB-binding sites. 16 A site-specific mutation was introduced into the NFjB-binding sites on PLD1 promoter by Quick Change Site-Directed Mutagenesis Kit (Stratagene, LaJolla, CA). For the mutagenic primer sequences, see Supporting Information Table I.…”

Section: Plasmids and Small Interfering Rnamentioning

confidence: 99%

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Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells

Kang

Park

Kim

et al. 2010

Intl Journal of Cancer

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Phospholipase D (PLD) is an important signaling enzyme implicated in the control of many biological processes, including cell proliferation and survival. Despite the importance of the duration and amplitude of PLD signaling in carcinogenesis, mechanisms that regulate PLD expression remain poorly understood. In our study, we define the regulatory components of the machinery that specifies selective PLD1 induction via signals propagated through PLD activity. We demonstrate for the first time that establishment of a positive feedback loop that is dependent on enzymatic activity originating from both PLD1 and PLD2 isozymes enhances selective expression of PLD1, but not PLD2. Phosphatidic acid, the product of PLD activity, leads to an increase in the Ras-ERK/PI3K-NFjB signaling cascade and enhances binding of NFjB to the PLD1 promoter, consequently inducing selective PLD1 expression in SK-BR3 breast cancer cells. Moreover, selective PLD inhibitor suppressed epidermal growth factor-induced matrix metalloproteinase upregulation and invasion by inhibiting PLD1 expression. In conclusion, we propose that autoregulation of PLD activity might be coupled to induction of PLD1 expression, and thereby play a role in carcinogenesis.Phosphatidic acid (PA) has emerged as an important mediator of lipid signaling that is associated with regulation of cell growth and proliferation, membrane trafficking and cytoskeletal reorganization. Because of its regulatory role, the level of PA itself should be tightly regulated through synthesis and turnover. PA is the product of phosphatidylcholine hydrolysis catalyzed by phospholipase D (PLD) and is strategically located at the intersection of several major signaling and metabolic pathways. Endogenous levels of PA are low in resting cells, and PLD activity is tightly regulated by mechanisms that control secretion, migration, survival and proliferation of cells. 1,2 PLD is activated by a variety of mitogens, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and interleukin 1b (IL-1b), [3][4][5][6][7] and its involvement in many cellular biological processes, including cell proliferation, survival, vesicular trafficking and secretion, has been demonstrated. 1,8 Two distinct isoforms of mammalian PLD, PLD1 and PLD2, have been identified. 9 PLD mediates the parallel reactions of phospholipid hydrolysis and transphosphatidylation. Primary alcohols, such as ethanol or 1-butanol, serve as competitive nucleophiles to water, resulting in a transphosphatidylation reaction that produces a phosphatidylalcohol, such as phosphatidylbutanol (PtdBut), instead of PA. Thus, primary alcohols have been used almost exclusively as the only means of preventing PA production for study of the role of PLD-mediated PA formation in certain cellular processes. 10 Potent dual PLD1 and PLD2 inhibitors, as well as isoformselective PLD inhibitors, with considerable pharmacological characterization have recently been developed. 11 Recent work has demonstrated a novel PA target in the Ras/Raf/ERK si...

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Section: Resultsmentioning

confidence: 99%

“…16,21 Zones of gelatinolytic activity were detected as clear bands against a blue background. Inverted images are presented.…”

Section: Zymographymentioning

confidence: 99%

Section: Plasmids and Small Interfering Rnamentioning

confidence: 99%

Section: Plasmids and Small Interfering Rnamentioning

confidence: 99%

See 2 more Smart Citations

Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells

Kang

Park

Kim

et al. 2010

Intl Journal of Cancer

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“…Both LPA and PA (Fig. 3A) are known to activate the MAPK and PI3K signaling pathways (29)(30)(31), and inhibition of CK in cells was shown to significantly decrease both pAKT and pERK levels (26). However, EDI3 knockdown in MCF-7 cells showed no effect on either pathway (Fig.…”

Section: Edi3 Positively Regulates Cell Migration In Vitro Via Pkcα Smentioning

confidence: 99%

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Stewart

Marchan

Lesjak

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

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Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.

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Mechanism of increased PLD1 gene expression during early adipocyte differentiation process of mouse cell line 3T3‐L1

Gao

Ito

Murakami

et al. 2009

J of Cellular Biochemistry

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A mouse cell line 3T3-L1 is differentiated into adipocytes when treated with an inducer cocktail (IDX) (insulin, dexametahsone, and a cAMP phosphodiesterase inhibitor of isobutyl-methylxanthine (IBMX)). Here, we report that PLD1, but not PLD2, mRNA and protein increased during the early differentiation process. Our analysis shows that IDX resulted in a sequential induction of C/EBPbeta, PLD1, and C/EBPalpha which is a key transcription factor of late adipocyte differentiation. Among the three inducers, IBMX + any other inducer induced mild adipocyte differentiation, whereas insulin + dexamethasone did not. IBMX increased PLD1 but not PLD2 mRNA. Forskolin, an adenylate cyclase activator, and dbcAMP also increased PLD1 mRNA, suggesting the cellular cAMP as the inducer of both adipocyte differentiation and PLD1 transcription. We focused on the regulatory mechanism of PLD1 transcription during this differentiation process. IDX or a combination of inducers including IBMX increased PLD1 promoter activity, which is consistent with mRNA analysis. Promoter analysis identified two adjacent C/EBP motifs located between -338 and -231 bp from the first exon as the IBMX responsive elements. Furthermore, overexpression of C/EBPbeta, but not C/EBPalpha, increased PLD1 mRNA and PLD1 5' promoter activity. EMSA and chromatin immunoprecipitation assay confirmed the direct binding of C/EBPbeta, but not C/EBPalpha, to these C/EBP motifs of PLD1 5' promoter. Our results show that PLD1 is a target gene of C/EBPbeta through the increased cellular cAMP during early adipocyte differentiation of 3T3-L1 cells.

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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

Cited by 70 publications

References 33 publications

Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells

Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Mechanism of increased PLD1 gene expression during early adipocyte differentiation process of mouse cell line 3T3‐L1

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