Cyclic phosphatidic acid influences the expression and regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 cells

Tsukahara, Tamotsu; Hanazawa, Shuwa; Murakami‐Murofushi, Kimiko

doi:10.1016/j.bbrc.2010.11.076

Cited by 7 publications

(12 citation statements)

References 34 publications

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“…However, the mechanism through which PDE3B is involved in intracellular cAMP production in response to cPA has remained unclear. We conducted this study on colon cancer cells using cPA, which had been shown previously to increase intracellular cAMP levels directly [8], a function of cPA that is also suggested by the anti-invasive properties of cPA [9]. We found that cPA inhibited the growth of HT-29 and LOVO cells, which express high levels of PDE3B, but not the growth of DLD-1 and Caco-2 cells, which express low levels of PDE3B.…”

Section: Discussionmentioning

confidence: 80%

“…We found that cPA inhibited the proliferation of HT-29 and LOVO cells but not of DLD-1 and Caco-2 cells (Figure 3A), which have lower endogenous levels of PDE3B than HT-29 and LOVO cells [8]. To test whether PDE3B affects the proliferation of HT-29 cells, PDE3B expression was knocked down using siRNAs.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we showed that cPA reduced intracellular triglyceride levels and inhibited PDE3B expression [8]. Moreover, intracellular cAMP levels in 3T3-L1 cells were found to increase after exposure to cPA.…”

Section: Introductionmentioning

confidence: 91%

“…Bioactive lipids such as cyclic phosphatidic acid (cPA) [7] [8] have been suggested to increase cellular cAMP levels and lead to RhoA inactivation in hepatoma cells [9]. Previously, we showed that cPA reduced intracellular triglyceride levels and inhibited PDE3B expression [8].…”

Section: Introductionmentioning

confidence: 99%

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Cyclic Phosphatidic Acid Stimulates cAMP Production and Inhibits Growth in Human Colon Cancer Cells

2013

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Colon cancer is a malignancy that develops in colon and rectal tissues. The prognosis for metastatic colon cancer remains poor, and novel therapeutic options are required to reduce colon cancer mortality. Recently, intracellular cAMP levels have been suggested to influence the behavior of cancer cells. Intriguingly, cyclic phosphatidic acid (cPA) and its structural analogs inhibit growth in many cancer cell lines, and our previous work has suggested that cPA increases cAMP production. Phosphodiesterase (PDE) type 3 isoforms PDE3A and PDE3B are expressed mainly in cardiovascular tissue and adipose tissue, respectively. Moreover, increase in intracellular cAMP levels has been associated with the inhibition of growth in colon cancer cells. These findings suggest that cPA could be used in colon cancer therapy. In this study, we found that cPA inhibited the growth of HT-29 cells, which express high levels of PDE3B, but not the growth of DLD-1 cells, which express low levels of PDE3B. Furthermore, cPA inhibited the phosphorylation of Akt in HT-29 cells in a dose-dependent fashion. Our results suggest that PDE3B expression and intracellular cAMP levels are correlated with the proliferation of colon cancer cells. These findings demonstrate for the first time that cPA may serve as a useful a molecule in targeted therapy for colon cancer.

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Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Cyclic Phosphatidic Acid Stimulates cAMP Production and Inhibits Growth in Human Colon Cancer Cells

2013

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“…CPA directly binds to PPARγ with nanomolar affinity and stabilizes the binding of a corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), to PPARγ — resulting in inhibition of PPARγ-related gene expression5152. CPA also inhibits phosphodiesterase 3B (PDE3B) expression and subsequently increases cAMP, leading to increased lipolysis in 3T3-L1 cells and an inhibition of adipogenesis53. Even though both PLD1 and PLD2 hydrolyze PC to produce PA, PLD1 is not involved in insulin-stimulated CPA production52.…”

Section: Discussionmentioning

confidence: 99%

PLD1 regulates adipogenic differentiation through mTOR - IRS-1 phosphorylation at serine 636/639

Song

Yoon

2016

Sci Rep

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Phospholipase D1 (PLD1) plays a known role in several differentiation processes, but its role in adipogenic differentiation remains unknown. In the present study, we identified PLD1 as a negative regulator of adipogenic differentiation. We showed that PLD activity was downregulated by both 3-Isobutyl-1-methylxanthine (IBMX) and insulin upon induction of differentiation in 3T3-L1 adipogenic cells. In line with this observation, PLD activity decreased in both high fat diet (HFD)-fed mice and ob/ob mice. We also found that differentiation of 3T3-L1 preadipocytes was enhanced by the depletion of PLD1 levels or inhibition of PLD1 activity by VU0155069, a PLD1-specific inhibitor. Conversely, treatment with phosphatidic acid (PA), a PLD product, and overexpression of PLD1 both caused a decrease in adipogenic differentiation. Moreover, the elevated differentiation in PLD1-knockdown 3T3-L1 cells was reduced by either PA treatment or PLD1 expression, confirming negative roles of PLD1 and PA in adipogenic differentiation. Further investigation revealed that PA displaces DEP domain-containing mTOR-interacting protein (DEPTOR) from mTORC1, which subsequently phosphorylates insulin receptor substrate-1 (IRS-1) at serine 636/639 in 3T3-L1 cells. Taken together, our findings provide convincing evidence for a direct role of PLD1 in adipogenic differentiation by regulating IRS-1 phosphorylation at serine 636/639 through DEPTOR displacement and mTOR activation.

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Short-term treatment with a 2-carba analog of cyclic phosphatidic acid induces lowering of plasma cholesterol levels in ApoE-deficient mice

Tsukahara

Haniu

Matsuda

et al. 2016

Biochemical and Biophysical Research Communications

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Plasma cholesterol levels are associated with an increased risk of developing atherosclerosis. An elevated low-density lipoprotein cholesterol (LDL-C) level is a hallmark of hypercholesterolemia in metabolic syndrome. Our previous study suggested that when acetylated LDL (AC-LDL) was co-applied with a PPARγ agonist, rosiglitazone (ROSI), many oil red O-positive macrophages could be observed. However, addition of cyclic phosphatidic acid (cPA) to ROSI-stimulated macrophages completely abolished oil red O-stained cells, indicating that cPA inhibits PPARγ-regulated AC-LDL uptake. This study aimed to determine whether metabolically stabilized cPA, in the form of a carba-derivative of cPA (2ccPA), could reduce plasma cholesterol levels and affect the expression of genes related to atherosclerosis in apolipoprotein E-knockout (apoE(-/-)) mice. 2ccPA reduced LDL-C levels in these mice (n = 3) from 460 to 330 mg/ml, from 420 to 350 mg/ml, and 420 to 281 mg/ml under a western-type diet. 2ccPA also reduced expression of lipid metabolism-related genes, cytokines, and chemokines in ApoE-deficient mice on a high-fat diet. Taken together, these results suggest that 2ccPA governs anti-atherogenic activities in the carotid arteries of apoE-deficient mice.

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Cyclic phosphatidic acid influences the expression and regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 cells

Cited by 7 publications

References 34 publications

Cyclic Phosphatidic Acid Stimulates cAMP Production and Inhibits Growth in Human Colon Cancer Cells

Cyclic Phosphatidic Acid Stimulates cAMP Production and Inhibits Growth in Human Colon Cancer Cells

PLD1 regulates adipogenic differentiation through mTOR - IRS-1 phosphorylation at serine 636/639

Short-term treatment with a 2-carba analog of cyclic phosphatidic acid induces lowering of plasma cholesterol levels in ApoE-deficient mice

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