scholarly journals Lysophosphatidic Acid Inhibits Simvastatin-Induced Myocytoxicity by Activating LPA Receptor/PKC Pathway

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1529 ◽  
Author(s):  
Kyung-Jong Won ◽  
Yu-Jin Goh ◽  
Sung-Hee Hwang
Keyword(s):  
Muscle Damage ◽  
Lysophosphatidic Acid ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Cell Toxicity ◽  
Xtt Assay ◽  
Lpa Receptor ◽  
L6 Cells ◽  
Kinase C ◽  
And Migration ◽  
Induced Apoptosis

Statins such as simvastatin have many side effects, including muscle damage, which is known to be the most frequent undesirable side effect. Lysophosphatidic acid (LPA), a kind of biolipid, has diverse cellular activities, including cell proliferation, survival, and migration. However, whether LPA affects statin-linked muscle damage has not been reported yet. In the present study, to determine whether LPA might exert potential protective effect on statin-induced myocyotoxicity, the effect of LPA on cytotoxicity in rat L6 myoblasts exposed to simvastatin was explored. Viability and apoptosis of rat L6 myoblasts were detected via 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5- [(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) assay and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, respectively. Protein expression levels were detected via Western blotting. Simvastatin decreased viability of L6 cells. Such decrease in viability was recovered in the presence of LPA. Treatment with LPA suppressed simvastatin-induced apoptosis in L6 cells. In addition, treatment with LPA receptor inhibitor Ki16425, protein kinase C (PKC) inhibitor GF109203X, or intracellular calcium chelator BAPTA-AM attenuated the recovery effect of LPA on simvastatin-induced L6 cell toxicity. These findings indicate that LPA may inhibit simvastatin-induced toxicity in L6 cells probably by activating the LPA receptor-PKC pathway. Therefore, LPA might have potential as a bioactive molecule to protect muscles against simvastatin-induced myotoxicity.

scholarly journals Primary human endothelial cells secrete agents that reduce responsiveness to lysophosphatidic acid (LPA)

2012 ◽  
Vol 32 (4) ◽  
pp. 393-400 ◽  
Author(s):  
Eun Young Park ◽  
Andrius Kazlauskas
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Lysophosphatidic Acid ◽  
Umbilical Vein ◽  
Vascular Endothelial ◽  
Human Endothelial Cells ◽  
Lpa Receptor ◽  
And Migration ◽  
Endothelial Growth Factor ◽  
Proliferation And Migration

The plasma level of LPA (lysophosphatidic acid) (200–600 nM) is well within the range that promotes proliferation and migration of vascular ECs (endothelial cells), yet vessels are quiescent and stable. In this report, we considered one explanation for this paradox: that ECs secrete agents that attenuate responsiveness to LPA. Indeed, we observed that CM (conditioned medium) from confluent, quiescent cultures of primary HUVECs (human umbilical vein ECs) contained an agent that inhibited LPA-mediated signalling events and cellular responses. The putative inhibitor, which we tentatively call ILMR (inhibitor of LPA-mediated responsiveness) seemed to act on cells (instead of at the level of LPA) by suppressing the ability of LPA receptor 1 to signal. The amount and/or activity of ILMR was regulated by growth factors; exposing HUVECs to VEGF-A (vascular endothelial growth factor A), but not bFGF (basic fibroblast growth factor), reduced the amount and/or activity of ILMR in CM. We conclude that in addition to promoting angiogenesis directly, VEGF-A can also act indirectly by modulating the bioactivity of angiomodulators such as LPA.

Lysophosphatidic Acid (LPA) Protects Primary Chronic Lymphocytic Leukemia (CLL) Cells from Apoptosis: Role for LPA as a Survival Factor in CLL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4788-4788
Author(s):  
Spencer B. Gibson ◽  
Xiaojie Hu ◽  
Neil Haney ◽  
Albert F. Kabore ◽  
James B. Johnston
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Protective Effect ◽  
Cell Line ◽  
Lysophosphatidic Acid ◽  
Lymphocytic Leukemia ◽  
Drug Induced ◽  
Lpa Receptor ◽  
Survival Factor ◽  
Induced Apoptosis ◽  
Primary Chronic Lymphocytic Leukemia

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD19+/CD5+ lymphocytes, and this is achieved primarily through a block in apoptosis. The mechanisms underlying this defect are not fully understood. Several proteins have been shown to protect CLL cells from apoptosis and one of these is albumin that solublizes lipids in the plasma. A lipid found in plasma, lysophosphatidic acid (LPA), protects epithelial and fibroblast cells from apoptosis. We investigated whether LPA could be a survival factor in CLL. Herein, we demonstrate that LPA effectively protects the B cell line BJAB and the CLL-like cell line I-83 from etoposide, fludarabine, and chlorambucil-induced apoptosis. In primary CLL cells, plasma from either healthy or CLL patients significantly reduces spontaneous and drug-induced apoptosis. However, delipidation of the plasma reduces its protective effect. In addition, LPA protects primary CLL cells but not healthy lymphocytes from apoptosis. By western blotting, the LPA receptor 1 (LPA1) expression is increased in primary CLL cells compared to normal lymphocytes. Treatment of primary CLL cells with the LPA receptor antagonist diacylglycerol pyrophosphate (DGPP) reverses the protective effect of LPA against apoptosis. Over expression of the LPA1 receptor protects cells from apoptosis and downregulation of the receptor blocks LPA mediated protection against spontaneous apoptosis. The protective effect of LPA is inhibited by blocking activation of the PI-3K/AKT signaling pathway. These results indicate that LPA is a survival factor in primary CLL cells and that drugs targeting the LPA receptors might be an effective therapy for this disease.

scholarly journals Activation of protein kinase C by lysophosphatidic acid: dependence on composition of phospholipid vesicles

1996 ◽  
Vol 317 (2) ◽  
pp. 583-588 ◽  
Author(s):  
Julianne J. SANDO ◽  
Olga I. CHERTIHIN
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Lysophosphatidic Acid ◽  
Lipid Membrane ◽  
Acyl Chain ◽  
Lipid Vesicles ◽  
Receptor Protein ◽  
Lpa Receptor ◽  
Kinase C ◽  
Pkc Activation

Lysophosphatidic acid (LPA) has attracted recent attention as a major serum-derived regulator implicated in responses to vascular injury and inflammation, in tumour invasiveness and in neuronal signalling and remodelling. Although the possibility of a specific G-protein-coupled LPA receptor protein has been suggested, characterization of such a receptor is lacking. Since LPA can activate protein kinase C (PKC) pathways in many cells and PKC activators mimic many LPA effects, the possibility of more direct LPA effects on PKC was investigated. Phosphatidylcholine (PC)/phosphatidylserine (PS)/diacylglycerol (DAG) lipid vesicles of defined acyl chain composition were used to activate the enzyme. At total concentrations of saturated PC/PS+DAG vesicles (2–3 mM) that provided maximal PKC activation, 1–10 mol% [18:1]-LPA led to a further approx. 2-fold activation of PKCα. At lower lipid concentrations, a greater increase was observed with LPA concentrations up to 16–20 mol%. Higher concentrations of LPA were inhibitory. The LPA activation of PKC was dependent on the presence of DAG, PS and Ca2+. [18:1]-Lysophosphatidylcholine produced similar PKC activation in PC/PS/DAG vesicles. [14:0]-LPA was less effective, and longer-chain saturated lysolipids were ineffective. In unsaturated PC/PS vesicles, very little to no effect of LPA was discernable. These results suggest that physiologically or pathologically relevant concentrations of LPA can contribute to PKC activation depending on the composition of the lipid membrane. We hypothesize that LPA may affect the formation of lipid domains that are recognized by the enzyme.

scholarly journals Lysophosphatidic Acid Triggers Apoptosis in HeLa Cells through the Upregulation of Tumor Necrosis Factor Receptor Superfamily Member 21

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Yunzhou Dong ◽  
Yong Wu ◽  
Mei-Zhen Cui ◽  
Xuemin Xu
Keyword(s):  
Tumor Necrosis Factor ◽  
Lysophosphatidic Acid ◽  
Hela Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Death Receptor ◽  
Dominant Negative ◽  
Lpa Receptor ◽  
Induced Apoptosis ◽  
Necrosis Factor

Lysophosphatidic acid (LPA), a naturally occurring bioactive phospholipid, activates G protein-coupled receptors (GPCRs), leading to regulation of diverse cellular events including cell survival and apoptosis. Despite extensive studies of the signaling pathways that mediate LPA-regulated cell growth and survival, the mechanisms underlying the apoptotic effect of LPA remain largely unclear. In this study, we investigated this issue in HeLa cells. Our data demonstrate that LPA induces apoptosis in HeLa cells at pathologic concentrations with a concomitant upregulation of the expression of TNFRSF21 (tumor necrosis factor receptor superfamily member 21), also known as death receptor number 6 (DR6) involved in inflammation. Moreover, treatment of cells with LPA receptor (LPAR) antagonist abolished the DR6 upregulation by LPA. LPA-induced DR6 expression was also abrogated by pertussis toxin (PTX), an inhibitor of GPCRs, and by inhibitors of PI3K, PKC, MEK, and ERK. Intriguingly, LPA-induced DR6 expression was specifically blocked by dominant-negative form of PKCδ(PKCδ-DN). LPA-induced DR6 expression was also dramatically inhibited by knockdown of ERK or CREB. These results suggest that activation of the MEK/ERK pathway and the transcription factor CREB mediate LPA-induced DR6 expression. More interestingly, knockdown of DR6 using siRNA approach remarkably attenuated LPA-induced apoptosis. In conclusion, our results suggest that LPA-induced apoptosis in HeLa cells is mediated by the upregulation of DR6 expression.

2133-P: Protein Kinase C Delta Mediates Cytokine-Induced Apoptosis in the Pancreatic Beta Cell

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 2133-P
Author(s):  
NIKKI L. FARNSWORTH ◽  
ROBERT A. PISCOPIO ◽  
RICHARD K. BENNINGER
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Protein Kinase C Delta ◽  
Kinase C ◽  
P Protein ◽  
Induced Apoptosis

scholarly journals Targeting the hallmarks of cancer: the effects of silibinin on proliferation, cell death, angiogenesis, and migration in colorectal cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Saba Sameri ◽  
Chiman Mohammadi ◽  
Mehrnaz Mehrabani ◽  
Rezvan Najafi
Keyword(s):  
Annexin V ◽  
Anticancer Activities ◽  
Scratch Assay ◽  
Anti Cancer ◽  
Different Types ◽  
Colon Cell ◽  
Colon Cell Line ◽  
And Migration ◽  
Induced Apoptosis ◽  
Colony Forming Assay

Abstract Background Silibinin, as a chemopreventive agent, has shown anti-cancer efficacy against different types of cancers. In the present study, we investigated the anti-cancer activities of silibinin on CT26 mouse colon cell line. Methods CT26 cells were treated with different concentrations of silibinin. To examine the cytotoxic effect of silibinin on proliferation, apoptosis, autophagy, angiogenesis, and migration, MTT, colony-forming assay, Annexin V/PI flow cytometry, RT-qPCR, and Scratch assay were used. Results Silibinin was found to significantly reduce CT26 cells survival. Furthermore, silibinin strongly induced apoptosis and autophagy by up-regulating the expression of Bax, Caspase-3, Atg5, Atg7 and BECN1 and down-regulating Bcl-2. Silibinin considerably down-regulated the expression of COX-2, HIF-1α, VEGF, Ang-2, and Ang-4 as well as the expression of MMP-2, MMP-9, CCR-2 and CXCR-4. Conclusions The present study revealed that silibinin shows anticancer activities by targeting proliferation, cell survival, angiogenesis, and migration of CT26 cells.

scholarly journals HBP1-mediated transcriptional repression of AFP inhibits hepatoma progression

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zhengyi Cao ◽  
Yuning Cheng ◽  
Jiyin Wang ◽  
Yujuan Liu ◽  
Ruixiang Yang ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcriptional Repression ◽  
Chinese Herb ◽  
Gene Promoter ◽  
Hepatoma Cells ◽  
Luciferase Assay ◽  
B Virus ◽  
And Migration ◽  
Induced Apoptosis ◽  
Common Malignancy

Abstract Background Hepatoma is a common malignancy of the liver. The abnormal high expression of alpha-fetoprotein (AFP) is intimately associated with hepatoma progress, but the mechanism of transcriptional regulation and singularly activation of AFP gene in hepatoma is not clear. Methods The expression of transcription factor HBP1 and AFP and clinical significance were further analyzed in hepatoma tissues from the patients who received surgery or TACE and then monitored for relapse for up 10 years. HBP1-mediated transcriptional regulation of AFP was analyzed by Western blotting, Luciferase assay, Realtime-PCR, ChIP and EMSA. After verified the axis of HBP-AFP, its impact on hepatoma was measured by MTT, Transwell and FACS in hepatoma cells and by tumorigenesis in HBP1−/− mice. Results The relative expressions of HBP1 and AFP correlated with survival and prognosis in hepatoma patients. HBP1 repressed the expression of AFP gene by directly binding to the AFP gene promoter. Hepatitis B Virus (HBV)-encoded protein HBx promoted malignancy in hepatoma cells through binding to HBP1 directly. Icaritin, an active ingredient of Chinese herb epimedium, inhibited malignancy in hepatoma cells through enhancing HBP1 transrepression of AFP. The repression of AFP by HBP1 attenuated AFP effect on PTEN, MMP9 and caspase-3, thus inhibited proliferation and migration, and induced apoptosis in hepatoma cells. The deregulation of AFP by HBP1 contributed to hepatoma progression in mice. Conclusions Our data clarify the mechanism of HBP1 in inhibiting the expression of AFP and its suppression in malignancy of hepatoma cells, providing a more comprehensive theoretical basis and potential solutions for the diagnosis and treatment of hepatoma.

scholarly journals Anti-neoplastic Effect of Ginkgolide C through Modulating c-Met Phosphorylation in Hepatocellular Carcinoma Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 8303
Author(s):  
Min Hee Yang ◽  
Seung Ho Baek ◽  
Jae-Young Um ◽  
Kwang Seok Ahn
Keyword(s):  
Hepatocellular Carcinoma ◽  
Invasion And Migration ◽  
Oncogenic Pathways ◽  
Tumor Growth And Metastasis ◽  
And Migration ◽  
Induced Apoptosis ◽  
Interfering Rna ◽  
Hepatocyte Growth ◽  
Hcc Cells ◽  
Met Phosphorylation

Ginkgolide C (GGC) derived from Ginkgo biloba, has been reported to exhibit various biological functions. However, the anti-neoplastic effect of GGC and its mechanisms in liver cancer have not been studied previously. Hepatocyte growth factor (HGF)/c-mesenchymal–epithelial transition receptor (c-Met) pathway can regulate tumor growth and metastasis in hepatocellular carcinoma (HCC) cells. This study aimed to evaluate the anti-neoplastic effect of GGC against HCC cells and we observed that GGC inhibited HGF-induced c-Met and c-Met downstream oncogenic pathways, such as PI3K/Akt/mTOR and MEK/ERK. In addition, GGC also suppressed the proliferation of expression of diverse tumorigenic proteins (Bcl-2, Bcl-xL, Survivin, IAP-1, IAP-2, Cyclin D1, and COX-2) and induced apoptosis. Interestingly, the silencing of c-Met by small interfering RNA (siRNA) mitigated c-Met expression and enhanced GGC-induced apoptosis. Moreover, it was noted that GGC also significantly reduced the invasion and migration of HCC cells. Overall, the data clearly demonstrate that GGC exerts its anti-neoplastic activity through modulating c-Met phosphorylation and may be used as an effective therapy against HCC.

Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4142-4151 ◽  
Author(s):  
Marcin Majka ◽  
Anna Janowska-Wieczorek ◽  
Janina Ratajczak ◽  
M. Anna Kowalska ◽  
Gaston Vilaire ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Phosphatidyl Inositol ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Proliferative Effect ◽  
Normal Human ◽  
And Migration ◽  
Induced Apoptosis

Abstract The role of the chemokine binding stromal-derived factor 1 (SDF-1) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin (TPO) have not been determined. In this study it was found that SDF-1, unlike TPO, does not stimulate αIIbβ3+ cell proliferation or differentiation or have an antiapoptotic effect. However, it does induce chemotaxis, trans-Matrigel migration, and secretion of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) by these cells, and both SDF-1 and TPO increase the adhesion of αIIbβ3+ cells to fibrinogen and vitronectin. Investigating the intracellular signaling pathways induced by SDF-1 and TPO revealed some overlapping patterns of protein phosphorylation/activation (mitogen-activated protein kinase [MAPK] p42/44, MAPK p38, and AKT [protein kinase B]) and some that were distinct for TPO (eg, JAK-STAT) and for SDF-1 (eg, NF-κB). It was also found that though inhibition of phosphatidyl-inositol 3-kinase (PI-3K) by LY294002 in αIIbβ3+ cells induced apoptosis and inhibited chemotaxis adhesion and the secretion of MMP-9 and VEGF, the inhibition of MAPK p42/44 (by the MEK inhibitor U0126) had no effect on the survival, proliferation, and migration of these cells. Hence, it is suggested that the proliferative effect of TPO is more related to activation of the JAK-STAT pathway (unique to TPO), and the PI-3K–AKT axis is differentially involved in TPO- and SDF-1–dependent signaling. Accordingly, PI-3K is involved in TPO-mediated inhibition of apoptosis, TPO- and SDF-1–regulated adhesion to fibrinogen and vitronectin, and SDF-1–mediated migration. This study expands the understanding of the role of SDF-1 and TPO in normal human megakaryopoiesis and indicates the molecular basis of the observed differences in cellular responses.

Sign in / Sign up

Export Citation Format

Share Document