Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 86
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Biochem Biophys Res Commun ; 722: 150162, 2024 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-38801802

RESUMO

Extracellular fatty acids (FAs) play an important role in regulating cellular functions such as cell proliferation, survival, and migration. The effects of oleic acid (OA) on cancer cells vary depending on the cell type. Our prior study showed that two distinct ovarian cancer cell lines, RMG-1 and HNOA, proliferate in response to OA, but they differ with respect to glucose utilization. Here, we aimed to elucidate the mechanism(s) by which OA stimulates proliferation of RMG-1 cells. We found that OA stimulates RMG-1 proliferation by activating the FA transporter CD36. OA also increases uptake of glucose and glutamine, which subsequently activate the pentose phosphate pathway (PPP) and glutamine metabolism, respectively. Given that ribose 5-phosphate derived from the PPP is utilized for glutamine metabolism and the subsequent de novo nucleotide synthesis, our findings suggest that OA affects the PPP associated with Gln metabolism, rather than glycolysis associated with glutaminolysis; this leads ultimately to activation of DNA synthesis, which is required for cell proliferation. This selective activation by OA contrasts with the mechanisms observed in HNOA cells, in which OA-induced cell proliferation is driven by transcriptional regulation of the GLUT gene. The diverse responses of cancer cells to OA may be attributed to distinct mechanisms of OA reception and/or different metabolic pathways activated by OA.


Assuntos
Proliferação de Células , Glutamina , Ácido Oleico , Neoplasias Ovarianas , Via de Pentose Fosfato , Glutamina/metabolismo , Via de Pentose Fosfato/efeitos dos fármacos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proliferação de Células/efeitos dos fármacos , Humanos , Linhagem Celular Tumoral , Feminino , Ácido Oleico/farmacologia , Ácido Oleico/metabolismo , Glucose/metabolismo
2.
Biochem Biophys Res Commun ; 657: 24-34, 2023 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-36965420

RESUMO

Fatty acids (FAs) play important roles in cell membrane structure maintenance, energy production via ß-oxidation, and as extracellular signaling molecules. Prior studies have demonstrated that exposure of cancer cells to FAs affects cell survival, cell proliferation, and cell motility. Oleic acid (OA) has somewhat controversial effects in cancer cells, with both pro- and anti-cancer effects, depending on cell type. Our prior findings suggested that OA enhances cell survival in serum starved HNOA ovarian cancer cells by activating glycolysis, but not ß-oxidation. Here, we pharmacologically examined the cellular mechanisms by which OA stimulates glycolysis in HNOA cells. OA induced cell cycle progression, leading to increase in cell number through peroxisome proliferator activated receptor (PPAR) α activation. OA-induced glycolysis was mediated by increased GLUT expression, and increases in GLUT expression were mediated by increased L-MYC expression. Furthermore, L-MYC expression was due to BRD4 activation. These findings suggested involvement of the BRD4-L-MYC-GLUT axis in OA-stimulated glycolysis. These results suggested that OA could activate PPARα to stimulate two pathways: glycolysis and cell cycle progression, and provided insight into the role of OA in ovarian cancer cell growth.


Assuntos
Neoplasias Ovarianas , PPAR alfa , Humanos , Feminino , PPAR alfa/metabolismo , Ácido Oleico/farmacologia , Proteínas Nucleares/metabolismo , Proteínas Facilitadoras de Transporte de Glucose , Fatores de Transcrição/metabolismo , Ácidos Graxos/metabolismo , Proliferação de Células , Proteínas de Ciclo Celular/metabolismo
3.
Biochem Biophys Res Commun ; 568: 1-7, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34166971

RESUMO

Lysophosphatidic acid (LPA) signaling plays diverse roles in the development of various vertebrates such as mammals and fish. The lamprey is a fish that retains ancestral features of vertebrates, but information regarding lamprey LPA receptor genes is limited. Here, using information from the lamprey genome database, we cloned two LPA receptor genes, Lpar1 and Lpar5, from the Japanese lamprey (Lethenteron camtschaticum). Lamprey Lpar1 had a high amino acid identity to mouse and medaka fish Lpar1, whereas Lpar5 amino acid sequences were more diverse between species. Our functional analyses using a heterologous expression system demonstrated that Lpar1 and Lpar5 responded to LPA treatment with G12/13-associated cellular responses, which are indicative of cytoskeletal actions. The existence of functional LPA receptors in the Japanese lamprey suggests that LPA receptor-dependent signals contribute to lamprey growth and development.


Assuntos
Proteínas de Peixes/genética , Lampreias/genética , Receptores de Ácidos Lisofosfatídicos/genética , Sequência de Aminoácidos , Animais , Citoesqueleto/genética , Citoesqueleto/metabolismo , Proteínas de Peixes/química , Proteínas de Peixes/metabolismo , Expressão Gênica , Japão , Lampreias/metabolismo , Lisofosfolipídeos/metabolismo , Receptores de Ácidos Lisofosfatídicos/química , Receptores de Ácidos Lisofosfatídicos/metabolismo
4.
Exp Cell Res ; 369(2): 316-324, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29859140

RESUMO

Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors mediates various biological effects in cancer cells. This study aimed to investigate the roles of LPA receptors in the regulation of cellular functions during tumor progression in osteosarcoma cells. Long-term cisplatin (CDDP)-treated MG63-C and MG63-R7-C cells were generated from osteosarcoma MG-63 and highly-migratory MG63-R7 cells, respectively. LPAR2 and LPAR3 expression levels were significantly higher in MG63-C cells than in MG-63 cells, while LPAR1 expression was reduced. MG63-C cells were highly motile, compared with MG-63 cells. MG63-C cell motility was suppressed by LPA2 knockdown and enhanced by the LPA1/LPA3 antagonist, dioctanoylglycerol pyrophosphate. LPAR2 and LPAR3 expression levels were significantly elevated in MG63-R7-C cells in comparison with MG63-R7 cells. MG63-R7-C cells were found to be highly invasive, correlating with metalloproteinase-2 activation. MG63-R7-C cells formed large colonies, whereas colony formation was absent from MG63-R7 cells. Notably, MG63-R7-C cell activities were inhibited by LPA2 knockdown. These results suggest that LPA signaling via LPA2 plays an important role in the acquisition of malignant properties during tumor progression in MG-63 cells.


Assuntos
Lisofosfolipídeos/metabolismo , Osteossarcoma/etiologia , Osteossarcoma/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Cisplatino/farmacologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Invasividade Neoplásica , Osteossarcoma/genética , Diester Fosfórico Hidrolases/metabolismo , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais , Ensaio Tumoral de Célula-Tronco
5.
Exp Cell Res ; 369(1): 54-60, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29750897

RESUMO

Free fatty acid receptor 1 (FFA1) and FFA4 mediate a variety of biological responses through binding of medium- and long-chain free fatty acids. The aim of this study was to investigate an involvement of FFA1 and FFA4 in the regulation of cellular functions during tumor progression in colon cancer cells. The long-term fluorouracil (5-FU) and cisplatin (CDDP) treated cells were generated from DLD1 cells (DLD-5FU and DLD-CDDP cells, respectively). FFAR1 expressions were lower in DLD-5FU and DLD-CDDP cells than in DLD1 cells. In contrast, DLD-5FU and DLD-CDDP cells showed the high FFAR4 expressions, compared with DLD1 cells. The cell motile activities of DLD-5FU and DLD-CDDP cells were reduced by GW9508 which is an agonist of FFA1 and FFA4. Moreover, GW1100, an antagonist of FFA1, inhibited the cell motile activities of DLD-5FU and DLD-CDDP cells. To evaluate whether FFA1 and FFA4 regulate the enhancement of cell motility, invasion and colony formation, highly migratory (hmDLD1) cells were established from DLD1 cells. FFAR1 expression was significantly higher in hmDLD1 cells than in DLD1 cells, but no change of FFAR4 expression was observed. The elevated cell motile and invasive activities and colony formation of hmDLD1 cells were suppressed by FFA1 inhibition. These results suggest that FFA1 and FFA4 are involved in the regulation of cellular functions during tumor progression in colon cancer DLD1 cells.


Assuntos
Movimento Celular/genética , Colo/patologia , Neoplasias do Colo/patologia , Células Epiteliais/fisiologia , Mucosa Intestinal/patologia , Receptores Acoplados a Proteínas G/fisiologia , Antineoplásicos/farmacologia , Benzoatos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/fisiopatologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Metilaminas/farmacologia , Propionatos/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores
6.
Biochem Biophys Res Commun ; 496(1): 225-230, 2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29309788

RESUMO

Lysophosphatidic acid (LPA) signaling through six subtypes of LPA receptors (LPA1 to LPA6) regulates a variety of biological responses in cancer cells. The aim of our study was to evaluate an involvement of LPA receptors in the activation of cell motility by phorbol ester and anticancer drug treatments in melanoma A375 cells. Cells were treated with 12-O-tetradecanoylphorbol- 13-acetate (TPA) and phorbol-12,13-dibutyrate (PDBu) for 3 days. The cell motile activity of TPA treated cells was significantly higher than that of PDBu treated cells, correlating with LPAR5 expression levels. LPA5 knockdown suppressed the high cell motile activity induced by TPA. To assess whether the cell motile activity of A375 cells is stimulated through LPA5 induced by anticancer drugs, the long-term cisplatin (CDDP) and dacarbazine (DTIC) treated cells were generated from A375 cells (A375-CDDP and A375-DTIC cells, respectively). The expression levels of LPA receptor genes were changed in A375-CDDP and A375-DTIC cells. In particular, CDDP and DTIC treatment markedly elevated LPAR5 expressions. The cell motile activities of A375-CDDP and A375-DTIC cells were significantly higher than that of untreated cells. These results suggest that the cell motile activity is regulated through the induction of LPA5 by phorbol ester and anticancer drug treatments in A375 cells.


Assuntos
Antineoplásicos/administração & dosagem , Movimento Celular/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Ésteres de Forbol/administração & dosagem , Receptores de Ácidos Lisofosfatídicos/metabolismo , Neoplasias Cutâneas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Neoplasias Cutâneas/tratamento farmacológico
7.
Biochem Biophys Res Commun ; 503(4): 2698-2703, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30093116

RESUMO

Lysophosphatidic acid (LPA) receptors (LPA1 to LPA6) regulate a variety of malignant properties in cancer cells. In the present study, we investigated the roles of LPA receptors in the promotion of cellular functions during tumor progression in fibrosarcoma cells. To obtain long-term anticancer drug treated cells, human fibrosarcoma HT1080 cells were treated with methotrexate (MTX) and cisplatin (CDDP) for 6 months. LPAR2 and LPAR5 expressions were significantly higher in MTX-treated (HT-MTX) cells than in HT1080 cells. The cell motile and invasive activities of HT-MTX cells were significantly elevated compared with HT1080 cells. Although LPAR5 expression was increased in MTX and CDDP treated (HT-M-C) cells, no change of LPAR2 expression was observed. The cell motile and invasive activities of HT-M-C cells were lower than those of HT1080 cells. Moreover, to evaluate whether LPA receptors promote cell invasive activity, highly invasion (HT1080-M6) cells were established from HT1080 cells. The cell invasive activity of HT1080-M6 cells was approximately 4.5 times higher than HT1080 cell invasion. LPAR2 expression was markedly elevated in HT1080-M6 cells compared with HT1080 cells. The high cell invasion activity of HT1080-M6 cells was significantly suppressed by an antagonist of LPA2, H2L5186303. These results suggest that LPA2 acts as a key regulator of malignant properties in HT1080 cells.


Assuntos
Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptores de Ácidos Lisofosfatídicos/genética , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Metotrexato/farmacologia , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais
8.
J Recept Signal Transduct Res ; 38(4): 311-315, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30111226

RESUMO

Free fatty acid (FFA) receptors belong to a member of G-protein-coupled receptors. GPCR 120 (GPR120) and GPR40 are identified as FFA receptors and activated via the binding of long- and medium-chain FFAs. The aim of this study was to assess the effects of GPR120 and GPR40 on cell motility and growth in breast cancer cells treated with tamoxifen (TAM). MCF-7 cells were continuously treated with TAM for approximately 6 months. The expression level of GPR40 gene was markedly higher in the long-term TAM treated (MCF-TAM) cells than in MCF-7 cells. In cell motility assay, MCF-TAM cells indicated the high cell motile activity, compared with MCF-7 cells. The cell motile activity of MCF-TAM cells was suppressed by a selective GPR40 antagonist, GW1100. To evaluate the effects of GPR40 on cell growth activity under estrogen-free conditions, cells were maintained in serum-free DMEM without phenol red for 2 days. In estrogen-free conditioned medium, the cell growth rate of MCF-TAM cells was significantly higher than that of MCF-7 cells. In addition, treatment of GW1100 reduced the cell growth rate of MCF-TAM cells. These results suggest that the cell motile and growth activities may be positively regulated through the induction of GPR40 by the long-term TAM treatment in MCF-7 cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética , Tamoxifeno/farmacologia , Benzoatos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Pirimidinas/farmacologia
9.
J Recept Signal Transduct Res ; 38(4): 367-371, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30396320

RESUMO

Lysophosphatidic acid (LPA) is a simple biological lipid and mediates several biological functions with LPA receptors (LPA1 to LPA6). In the present study, to assess whether LPA receptors promote cell-invasive activity of pancreatic cancer cells, highly invasion PANC-R9 cells were established from PANC-1 cells, using Matrigel-coated Cell Culture Insert. The cell-invasive activity of PANC-R9 cells was shown to be approximately 15 times higher than that of PANC-1 cells. LPAR1 expression level was markedly elevated in PANC-R9 cells in comparison with PANC-1 cells, while LPAR3 expression level was reduced. The cell-invasive activity of PANC-R9 cells was enhanced by LPA, but LPA had no impact on PANC-1 cell invasion. Before initiation of the cell invasion assay, PANC-R9 cells were pretreated with dioctanoylglycerol pyrophosphate (DGPP), an antagonist of LPA1/LPA3. The invasive activity of PANC-R9 cells was markedly suppressed by DGPP. Autotaxin (ATX) is a key enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to LPA. ATX expression level was elevated in PANC-R9 cells compared with PANC-1 cells. In the presence of LPC, the cell motile activity of PANC-R9 cells was markedly stimulated. In contrast, LPC did not affect the cell motile activity of PANC-1 cells. PANC-R9 cell motility was inhibited by an ATX inhibitor, PF-8380. These results suggest that LPA signaling via LPA1 is a potent molecular target for the regulation of tumor progression in PANC-1 cells.


Assuntos
Lisofosfatidilcolinas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Diester Fosfórico Hidrolases/genética , Receptores de Ácidos Lisofosfatídicos/genética , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Lisofosfatidilcolinas/genética , Invasividade Neoplásica/genética , Neoplasias Pancreáticas/genética , Ácidos Fosfatídicos/metabolismo , Piperazinas/farmacologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
J Recept Signal Transduct Res ; 38(1): 71-75, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29369010

RESUMO

Lysophosphatidic acid (LPA) is a simple physiological lipid and exhibits a variety of cellular responses via the activation of G protein-coupled transmembrane LPA receptors (LPA receptor-1 (LPA1) to LPA6). The aim of our study was to investigate effects of LPA receptors on soft agar colony formation in colon cancer cells treated with anticancer drugs. DLD1 cells were treated with fluorouracil (5-FU) or cisplatin (CDDP) for at least six months (DLD-5FU and DLD-CDDP cells, respectively). LPAR1 gene expression was markedly elevated in DLD-5FU cells. In contrast, DLD-CDDP cells showed the high expression of LPAR6 gene. In colony formation assay, DLD-5FU cells formed markedly large-sized colonies, while no colony formation was observed in DLD1 and DLD-CDDP cells. The large-sized colonies formed in DLD-5FU cells were suppressed by LPA1 knockdown. In contrast, LPA6 knockdown increased the size of colonies. In addition, DLD-5FU cells were further treated with CDDP for three months (DLD-C-F cells). DLD-CDDP cells were also treated with 5-FU (DLD-F-C cells). DLD-C-F cells formed large-sized colonies, but not DLD-F-C cells, correlating with LPAR1 and LPAR6 gene expression levels. These results suggest that LPA1 and LPA6 may regulate the colony formation activity in DLD1 cells treated with anticancer drugs.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Receptores de Ácidos Lisofosfatídicos/genética , Células-Tronco/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Fluoruracila/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lisofosfolipídeos/genética , Lisofosfolipídeos/metabolismo
11.
Exp Cell Res ; 352(1): 139-145, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28189636

RESUMO

Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors exhibits a variety of biological effects, such as cell proliferation, motility and differentiation. The aim of this study was to evaluate the roles of LPA1 and LPA3 in cellular functions during tumor progression in pancreatic cancer cells. LPA1 and LPA3 knockdown cells were generated from PANC-1 cells. The cell motile and invasive activities of PANC-1 cells were inhibited by LPA1 and LPA3 knockdown. In gelatin zymography, LPA1 and LPA3 knockdown cells indicated the low activation of matrix metalloproteinase-2 (MMP-2) in the presence of LPA. Next, to assess whether LPA1 and LPA3 regulate cellular functions induced by anticancer drug, PANC-1 cells were treated with cisplatin (CDDP) for approximately 6 months. The cell motile and invasive activities of long-term CDDP treated cells were markedly higher than those of PANC-1 cells, correlating with the expression levels of LPAR1 and LPAR3 genes. In soft agar assay, the long-term CDDP treated cells formed markedly large sized colonies. In addition, the cell motile and invasive activities enhanced by CDDP were significantly suppressed by LPA1 and LPA3 knockdown as well as colony formation. These results suggest that LPA signaling via LPA1 and LPA3 play an important role in the regulation of cellular functions during tumor progression in PANC-1 cells.


Assuntos
Lisofosfolipídeos/farmacologia , Neoplasias Pancreáticas/patologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Progressão da Doença , Quimioterapia Combinada , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
12.
Biochem Biophys Res Commun ; 486(3): 767-773, 2017 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-28342860

RESUMO

Lysophosphatidic acid (LPA), an extracellular lipid mediator, exerts various cellular effects through activation of LPA receptors, LPA1-LPA6, in many types of cells including cancer cells. We recently found several missense mutations of Lpar1 in rat cancer tissues. One of these mutations is located at the extracellular tip of the seventh transmembrane domain of LPA1, and another three mutations are found within the NPXXY motif in the seventh transmembrane domain. These mutants are designated F295S LPA1 and P308S, I310T, and Y311H LPA1, respectively. Here, we examined the functions of these LPA1 mutants. Compared with wild-type (WT) LPA1, F295S, P308S, and I310T LPA1 showed decreased maximal responses in inhibition of cAMP formation, Ca2+ mobilization, and cytoskeletal changes. Y311H LPA1 failed to show LPA-induced cellular responses. However, these LPA1 mutants were internalized in response to LPA exposure. Finally, while WT and F295S LPA1 showed a similar, broad distribution throughout the cell, P308S, I310T, and Y311H LPA1 displayed a restricted cellular distribution and co-localized with the endoplasmic reticulum. These data suggest that the LPA1 mutants perturb LPA signaling in cancer tissues.


Assuntos
Hepatócitos/metabolismo , Lisofosfolipídeos/metabolismo , Mutação , Neurônios/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Motivos de Aminoácidos , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Citoesqueleto/metabolismo , Citoesqueleto/ultraestrutura , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Expressão Gênica , Hepatócitos/ultraestrutura , Neurônios/ultraestrutura , Domínios Proteicos , Ratos , Receptores de Ácidos Lisofosfatídicos/química , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais
13.
Biochem Biophys Res Commun ; 493(1): 468-473, 2017 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-28882592

RESUMO

Free fatty acids not only play a role in cell membrane construction and energy production but also exert diverse cellular effects through receptor and non-receptor mechanisms. Moreover, epidemiological and clinical studies have so far suggested that polyunsaturated fatty acids (PUFAs) could have health benefits and the advantage as therapeutic use in cancer treatment. However, the underlying mechanisms of PUFA-induced cellular effects remained to be cleared. Here, we examined the effects of ω-3 and ω-6 PUFAs on cell death in ovarian cancer cell lines. ω-3 PUFA, docosahexaenoic acid (DHA) and ω-6 PUFA, γ-linolenic acid (γ-LNA) induced cell death in KF28 cells at the levels of physiological concentrations, but not HAC2 cells. Pharmacological and biochemical analyses demonstrated that cell death induced by DHA and γ-LNA was correlated with activation of JNK and p38 MAP kinases, and further an upstream MAP kinase kinase, apoptosis signal-regulating kinase 1, which is stimulated by reactive oxygen species (ROS). Furthermore, an antioxidant vitamin E attenuated PUFA-induced cell death and MAP kinase activation. These findings indicate that PUFA-induced cell death involves ROS-dependent MAP kinase activation and is a cell type-specific action. A further study of the underlying mechanisms for ROS-dependent cell death induced by PUFAs will lead to the discovery of a new target for cancer therapy or diagnosis.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Graxos Insaturados/administração & dosagem , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
14.
Biochem Biophys Res Commun ; 484(3): 675-680, 2017 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-28159555

RESUMO

G-protein-coupled receptor 120 (GPR120) and GPR40 are members of free fatty acid (FFA) receptors and mediate a variety of biological responses through binding of medium- and long-chain FFAs. Recently, it has been reported that GPR120 and GPR40 regulated cellular functions of cancer cells. In the present study, to assess whether GPR120 and GPR40 are involved in the enhancement of cell motile activity of osteosarcoma cells, we established highly migratory (MG63-R7) cells from osteosarcoma MG-63 cells. The expression level of GPR120 gene was significantly higher in MG63-R7 cells than in MG-63 cells, while no change of GPR40 expression was observed. In cell motility assay, the cell motile activity of MG63-R7 cells was approximately 200 times higher than that of MG-63 cells. The cell motile activity of MG63-R7 cells was stimulated by GW9508, which is an agonist of GPR120 and GPR40. Moreover, a GPR40 antagonist GW1100 elevated the cell motile activity of MG63-R7 cells in the presence of GW9508. To confirm the effects of GPR120 and GPR40 on the cell motile activity of MG63-R7 cells, GPR120 knockdown cells were generated from MG63-R7 cells. The cell motile activity of MG63-R7 cells was markedly suppressed by GPR120 knockdown. These results indicated that GPR120 enhanced and GPR40 inhibited the cell motile activity of highly migratory osteosarcoma cells.


Assuntos
Movimento Celular , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Receptores Acoplados a Proteínas G/metabolismo , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica
15.
Biochem Biophys Res Commun ; 483(1): 652-657, 2017 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-27993681

RESUMO

Lysophosphatidic acid (LPA) is an extracellular biological lipid and interacts with six subtypes of G protein-coupled LPA receptors (LPA1 to LPA6). LPA receptors exhibit a variety of cellular functions, depending on types of cancer cells. In this study, to assess the roles of LPA4 and LPA6 in cell growth and motile activities of colon cancer cells, LPA4 and LPA6 knockdown cells were established from DLD1 and HCT116 cells. LPA treatment increased the cell growth activities of LPA4 and LPA6 knockdown cells, compared with control cells. The cell motile activities of LPA4 and LPA6 knockdown cells were significantly higher than those of control cells. To evaluate the effects of LPA4 and LPA6 on cell motile activity induced by anticancer drug, long-term fluorouracil (5-FU) treated (DLD-5FU) cells were generated. The expression levels of LPAR1, LPAR4 and LPAR6 genes were significantly increased in DLD-5FU cells. DLD-5FU cells showed the high cell motile activity, compared with DLD1 cells. The increased cell motile activity was markedly stimulated by LPA4 and LPA6 knockdown. In contrast, the cell motile activity enhanced by 5-FU treatment was suppressed by LPA1 knockdown. These results suggest that LPA signaling via LPA4 and LPA6 negatively regulates the cell motile activities of DLD1 and HCT116 cells as well as long-term 5-FU treated cells.


Assuntos
Neoplasias do Colo/patologia , Lisofosfolipídeos/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores Purinérgicos/metabolismo , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Fluoruracila/farmacologia , Células HCT116 , Humanos , Lisofosfolipídeos/farmacologia , Receptores Purinérgicos P2 , Transdução de Sinais
16.
Mol Cell Biochem ; 431(1-2): 29-35, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28205098

RESUMO

Lysophosphatidic acid (LPA) is a simple biophysical lipid which interacts with at least six subtypes of G protein-coupled LPA receptors (LPA1-LPA6). In cancer cells, LPA signaling via LPA receptors is involved in the regulation of malignant properties, such as cell growth, motility, and invasion. The aim of this study was to assess whether LPA receptors regulate cellular functions of fibrosarcoma cells treated with anticancer drug. HT1080 cells were maintained by the stepwise treatment of cisplatin (CDDP) at a range of 0.01 to 1.0 µM for approximately 6 months. The cell motile and invasive activities of long-term CDDP-treated (HT-CDDP) cells were significantly stimulated by LPA treatment, while HT-CDDP cells in the static state showed the low cell motile and invasive activities in comparison with HT1080 cells. Since the expression level of LPAR2 gene was markedly elevated in HT-CDDP cells, LPA2 knockdown cells were generated from HT-CDDP cells. The cell motile and invasive activities of HT-CDDP cells were reduced by LPA2 knockdown. In colony assay, large-sized colonies formed by long-term CDDP treatment were suppressed by LPA2 knockdown. In addition, LPA2 knockdown cells reduced LPA production by autotaxin (ATX), correlating with ATX expression level. These results suggest that LPA signaling via LPA2 may play an important role in the regulation of cellular functions in HT1080 cells treated with CDDP.


Assuntos
Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Fibrossarcoma/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/biossíntese , Receptores de Ácidos Lisofosfatídicos/biossíntese , Movimento Celular/genética , Fibrossarcoma/genética , Fibrossarcoma/patologia , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Diester Fosfórico Hidrolases/biossíntese , Diester Fosfórico Hidrolases/genética , Receptores de Ácidos Lisofosfatídicos/genética
17.
Exp Cell Res ; 342(2): 193-9, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26968637

RESUMO

Free fatty acids (FFAs) are dietary nutrients which mediate a variety of biological effects through binding to G-protein-coupled FFA receptors (FFARs). G-protein-coupled receptor 120 (GPR120) and GPR40 are identified as FFARs for long- and medium-chain fatty acids. Here we investigated whether GPR120 and GPR40 are involved in the acquisition of malignant properties in lung cancer cells. Three lung cancer RLCNR, LL/2 and A549 cells used in this study expressed GPR120 and GPR40 genes. The cell motile activities of all cells were significantly suppressed by a GPR40 antagonist GW1100. In addition, GPR40 knockdown inhibited the cell motile activity of A549 cells. In gelatin zymography, matrix metalloproteinase-2 (MMP-2) activity in GPR40 knockdown was significantly lower than that in control cells. Next, to evaluate effects of GPR120 and GPR40 on cellular functions induced by anti-cancer drug, the long-term cisplatin (CDDP) treated (A549-CDDP) cells were generated. The expression levels of GPR120 and GPR40 were significantly decreased in A549-CDDP cells. While A549-CDDP cells showed the high cell motile activity, GW1100 suppressed the cell motile activity of A549-CDDP cells. These results demonstrate that GPR120 negatively and GPR40 positively regulate cellular functions during tumor progression in lung cancer cells.


Assuntos
Receptores Acoplados a Proteínas G/fisiologia , Animais , Antineoplásicos/farmacologia , Benzoatos/farmacologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Cisplatino/farmacologia , Células Endoteliais/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metilaminas/farmacologia , Camundongos , Propionatos/farmacologia , Pirimidinas/farmacologia , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores
18.
Biochem Biophys Res Commun ; 475(1): 25-30, 2016 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-27163640

RESUMO

G-protein-coupled receptor 120 (GPR120) and GPR40 exhibit a variety of biological responses by the binding of free fatty acids. 12-O-Tetradecanoylphorbol-13-acetate (TPA) is a tumor promoting agent of skin carcinogenesis. It is known that TPA treatment stimulates cell motile activity of cancer cells, including melanoma cells. In the present study, we investigated whether GRP120 and GPR40 are involved in regulation of cell motile activity induced by TPA in two melanoma cell lines. A375 and G361 cells were treated with TPA at a concentration of 10 nM for 24 h. The cell motile activity of A375 cells was significantly increased by TPA, correlating with GPR40 expression. In contrast, TPA suppressed the cell motile activity of G361 cells, while GPR120 and GPR40 expressions were increased. The cell motile activity of A375 cells treated with TPA was markedly increased by GPR120 knockdown. In addition, to assess roles of GPR120 and GPR40 in cellular functions of A375 cells by the long-term TPA treatment, cells were treated with TPA (1 nM) for at least 3 months. The long-term TPA treatment induced the high cell motile activity and elevated GPR120 and GPR40 expressions. The high cell motile activity of A375 cells stimulated by the long-term TPA treatment was enhanced by GPR120 knockdown. These results suggest that GPR120 negatively and GPR40 positively regulate cell motile activities induce by TPA in melanoma cells.


Assuntos
Carcinógenos/metabolismo , Melanoma/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Cutâneas/metabolismo , Acetato de Tetradecanoilforbol/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Melanoma/genética , Melanoma/patologia , Receptores Acoplados a Proteínas G/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
19.
Mol Carcinog ; 55(11): 1553-1559, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26331585

RESUMO

G-protein-coupled receptor 40 (GPR40) and GPR120 mediate a variety of biological functions by the binding of long and medium chain free fatty acids. In the present study, we investigated a role of GPR40 in the pathogenesis of fibrosarcoma HT1080 cells. The GPR40 gene expression was detected in HT1080 cells, but not the GPR120 gene. The cell motile and invasive activities were markedly enhanced by GPR40 knockdown, compared with control cells. To evaluate whether GPR40 is involved in the cellular functions of HT1080 cells during anticancer drug treatment, HT1080 cells were maintained in condition medium containing cisplatin (CDDP) (0.01-1.0 µM) for 6 mo. The expression levels of the GPR40 gene was elevated by the long-term CDDP treatment in HT1080 cells, while the GPR120 gene expression remained unchanged. The cell motile and invasive activities of HT1080 cells treated with CDDP were significantly lower than those of untreated cells. In gelatin zymography, the activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 of HT1080 cells were enhanced by the long-term CDDP treatment. In addition, GW9508 which is an agonist of GPR40 and GPR120 suppressed the cell motile and invasive activities of HT1080 cells treated with CDDP as well as the MMP activation. These results suggest that GPR40 negatively regulates the tumor progression of fibrosarcoma cells. © 2015 Wiley Periodicals, Inc.


Assuntos
Cisplatino/farmacologia , Fibrossarcoma/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica
20.
Mol Carcinog ; 55(11): 1573-1583, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26377854

RESUMO

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA1 to LPA6 ) mediates a variety of cellular functions, including cell motility. In the present study, we investigated the effects of LPA receptors on cell motile activity during multi-stage hepatocarcinogenesis in rat liver epithelial WB-F344 cells treated with chemical liver carcinogens. Cells were treated with a initiator (N-nitrosodiethylamine (DEN)) and three promoters (phenobarbital (PB), okadaic acid (OA) and clofibrate) every 24 h for 2 days. Cell motile activity was elevated by DEN, correlating with Lpar3 expression. PB, OA, and clofibrate elevated Lpar1 expression and inhibited cell motile activity. To evaluate the effects of long-term treatment on cell motility, cells were treated with DEN and/or PB for at least 6 months. Lpar3 expression and cell motile activity were significantly elevated by the long-term DEN treatment with or without further PB treatment. In contrast, long-term PB treatment with or without further DEN elevated Lpar1 expression and inhibited cell motility. When the synthesis of extracellular LPA was blocked by a potent ATX inhibitor S32826 before cell motility assay, the cell motility induced by DEN and PB was markedly suppressed. These results suggest that activation of the different LPA receptors may regulate the biological functions of cells treated with chemical carcinogens. © 2015 Wiley Periodicals, Inc.


Assuntos
Carcinógenos/farmacologia , Dietilnitrosamina/efeitos adversos , Células Epiteliais/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Clofibrato/efeitos adversos , Clofibrato/farmacologia , Células Epiteliais/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/induzido quimicamente , Ácido Okadáico/efeitos adversos , Ácido Okadáico/farmacologia , Fenobarbital/efeitos adversos , Fenobarbital/farmacologia , Ratos , Ratos Endogâmicos F344
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA