Critical Role of Peroxisome Proliferator-Activated Receptor γ on Anoikis and Invasion of Squamous Cell Carcinoma

Masuda, Takayuki; Wada, Koichiro; Nakajima, Atsushi; Okura, Masaya; Kudo, Chiho; Kadowaki, Takashi; Kogo, Mikihiko; Kamisaki, Yoshínori

doi:10.1158/1078-0432.ccr-05-0087

Cited by 54 publications

(98 citation statements)

References 37 publications

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“…In the present study, the endogenous and exogenous PPAR-g ligands 15-PGJ 2 and ciglitazone, respectively, dose-dependently inhibited pancreatic cancer cell invasion, further supporting the notion of PPAR-g ligands as being potentially therapeutic agents in pancreatic cancer. There is now accumulating evidence that PPAR-g ligands possess potent anti-invasive properties in human cancers (29)(30)(31). Our findings that PPAR-g ligands decreased uPA and increased PAI-1 levels in pancreatic cancer cells, thereby substantially reducing overall urokinase activity, strongly suggested that the anti-invasive properties of PPAR-g ligands were mediated by modulating the plasminogen activator system.…”

Section: Discussionmentioning

confidence: 65%

Activation of Peroxisome Proliferator-Activated Receptor-γ Decreases Pancreatic Cancer Cell Invasion through Modulation of the Plasminogen Activator System

Sawai¹,

Liu

Reber³

et al. 2006

Molecular Cancer Research

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Cancer cell invasion and metastasis require the concerted action of several proteases that degrade extracellular matrix proteins and basement membranes. Recent reports suggest the plasminogen activator system plays a critical role in pancreatic cancer biology. In the present study, we determined the contribution of the plasminogen activator system to pancreatic cancer cell invasion in vitro. Moreover, the effect of peroxisome proliferatoractivated receptor (PPAR)-; ligands, which are currently in clinical use as antidiabetic drugs and interestingly seem to display antitumor activities, on pancreatic cancer cell invasion and the plasminogen activator system was assessed. Expression of components of the plasminogen activator system [i.e., urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1, and uPA receptor] was detected in six human pancreatic cancer cell lines. Inhibition of urokinase activity by specific synthetic compounds reduced baseline pancreatic cancer cell invasion. The PPAR-; ligands 15-deoxy-# 12,14 -prostaglandin J 2 and ciglitazone also attenuated pancreatic cancer cell invasion. This effect was abrogated by dominant-negative PPAR-; receptors and pharmacologic PPAR-; inhibitors. Moreover, activation of PPAR-; by ligands increased plasminogen activator inhibitor-1 and decreased uPA levels in pancreatic cancer cells, and this was accompanied by a reduction in total urokinase activity. The present study shows that the plasminogen activator system plays an integral role in pancreatic cancer cell invasion in vitro. Activation of the nuclear receptor PPAR-; by ligands reduced pancreatic cancer cell invasion, which was largely mediated by modulation of the plasminogen activator system. These findings further underscore the potential role of PPAR-; ligands as therapeutic agents in pancreatic cancer. (Mol Cancer Res 2006;4(3):159-67)

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Section: Discussionmentioning

confidence: 65%

Activation of Peroxisome Proliferator-Activated Receptor-γ Decreases Pancreatic Cancer Cell Invasion through Modulation of the Plasminogen Activator System

Sawai¹,

Liu

Reber³

et al. 2006

Molecular Cancer Research

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“…Cells were maintained in DMEM containing 10% fetal bovine serum (FBS) at 37˚C under 0.5% CO 2 . For the cell growth experiment, cells were trypsinized and replated onto culture dishes (11)(12)(13)(14)(15)17,18). SCC cells were counted using a Countess Automated Cell Counter (Invitrogen, Eugene, OR, USA).…”

Section: Antibodiesmentioning

confidence: 99%

“…Therefore, increased FABP4 expression may affect the growth of various tumor types. Our research group also reported that molecules controlled by peroxisome proliferator-activated receptor γ (PPARγ) play key roles in SCC growth (11)(12)(13)(14)(15). As FABP4 is known to mediate transcription with PPARγ (4,16), we hypothesized that FABP4 may regulate SCC growth.…”

Section: Introductionmentioning

confidence: 97%

Expression of fatty acid binding protein 4 is involved in the cell growth of oral squamous cell carcinoma

et al. 2014

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Abstract. Fatty acid binding proteins (FABPs) are a family of small and highly conserved lipid chaperone molecules with highly varied functions. Among them, fatty acid binding protein 4 (FABP4, also known as aP2) is highly expressed by adipocytes, macrophages and dendritic cells. Although the role of FABP4 in cancer is still unclear, it has been reported to be highly expressed by human tumors such as ovarian and bladder cancers. In the present study, we investigated the expression and role of FABP4 in oral squamous cell carcinoma (SCC) and its expression in oral SCC tissues. Immunohistochemical staining revealed that FABP4 expression in the tumor tissue was much higher than that in the non-tumor area of the same specimen. In the in vitro studies, an FABP4-knockdown SCC cell line (established through FABP4-specific siRNA) showed inhibited growth, and inhibited expression and activation of mitogen-activated protein kinase (MAPK). These results indicate that expression of FABP4 plays an important role in the cell growth of oral SCC through the MAPK pathway. IntroductionOral squamous cell carcinoma (SCC) is a major neoplasm of the oral cavity with an increasing rate of incidence (1-3). The optimal therapy for early oral SCC is surgery, but the overall survival rate has exhibited only a slight change (1-3). Therefore, more effective therapies for oral SCC are needed.Fatty acid binding proteins (FABPs) are a family of small and highly conserved lipid chaperone molecules that bind long-chain fatty acids and other hydrophobic ligands. Their functions are wide ranging (4-6). Among them, fatty acid binding protein 4 (FABP4, also known as aP2) is highly expressed in adipocytes, macrophages and dendritic cells (5,7). As a result of its distribution, FABP4 is the most extensively researched FABP in endocrinology and metabolomics. FABP4 affects metabolic syndrome progression; FABP4-deficient mice were found to have reduced hyperinsulinemia and insulin resistance in obesity (7,8) and showed protection from atherosclerosis (9).However, little is known concerning the role of FABP4 in cancer, including oral SCC. Recently, Nieman et al (10) reported that adipocytes promote ovarian cancer metastasis and tumor cell growth by providing energy mediated by FABP4. Therefore, increased FABP4 expression may affect the growth of various tumor types. Our research group also reported that molecules controlled by peroxisome proliferator-activated receptor γ (PPARγ) play key roles in SCC growth (11-15). As FABP4 is known to mediate transcription with PPARγ (4,16), we hypothesized that FABP4 may regulate SCC growth. Therefore, in the present study, we investigated FABP4 expression and its effects on SCC of the tongue. Materials and methodsTissue samples. All clinical studies were approved by the Ethics Committee of Osaka University Dental Hospital, Osaka. Twenty-seven SCC specimens from resected tongue tissue were obtained at the Osaka University Dental Hospital during 1986-2008 after patient informed consent (Table I). Patients received no pre...

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“…3-(4,5-dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide assay was processed as described previously (20). For Western blot assay, cells were allowed to adhere to FN-coated plates for 2 h, and then proteins were collected.…”

Section: Transfection and Selection Of Stably Transfected Hepg2/ Mr-1mentioning

confidence: 99%

MR-1 Modulates Proliferation and Migration of Human Hepatoma HepG2 Cells through Myosin Light Chains-2 (MLC2)/Focal Adhesion Kinase (FAK)/Akt Signaling Pathway

Ren

Jin

Bian

et al. 2008

Journal of Biological Chemistry

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The key of cell migration process on solid substrates is phosphorylation of myosin light chain-2 (MLC2), which is implicated in a variety of intracellular functions. The previous data show that MLC2 interacts with a novel human gene, myofibrillogenesis regulator 1 (MR-1). Here, we reported that MR-1 was specially overexpressed in human hepatoma HepG2 cells. Transient treatment of cells with small interfering RNA (siRNA) against MR-1 or stable transfection of cells with plasmid expressing MR-1-siRNA led to inhibitions of cell proliferation, migration, and adhesion. Following down-regulation of MR-1, the phosphorylations of MLC2, focal adhesion kinase (FAK), and Akt were dramatically decreased, and the formation of stress fiber was destroyed by MR-1-siRNAs in hepatoma HepG2 cells. In addition, exogenous MR-1-induced as well as inherent phosphorylations of FAK and Akt were decreased by MLC kinase (MLCK) inhibitor, and F-actin polymerization inhibitor also decreased phosphorylations of FAK and Akt. Correspondingly, MR-1-enhanced migration of cells was also inhibited by these two inhibitors. These indicated that MLC2 activation and intact actin cytoskeleton were pivotal for MR-1 function. In vivo data showed that MR-1-siRNA markedly inhibited growth of human HepG2. This study suggested that overexpression of MR-1 was associated with cancer cell proliferation and migration through MLC2 and that MR-1 might be a potential cancer therapeutic target.Cancer progression from a primary tumor to secondary metastasis is a highly complex process involving alteration of gene expression, acquisition of cell motility, interaction with extracellular matrix (ECM), 3 change in cell adhesion, and expression of ECM-degrading protease (1). Cell migration is a critical step in tumor metastasis. Cancer cells move within tissues during invasion and metastasis by their own motility, and cell migration involves multiple processes that are regulated by various signaling molecules (2). It results from a dynamic interplay between the substrate and cytoskeleton protein located at the focal adhesion complex (3). It is known that cells exert force propelling the cell forward by contraction of the actin cytoskeleton through activation of myosin II (4). The actin-myosin II interaction in non-muscle cells is regulated by the phosphorylation of MLC2 at serine-19 (5). MLC2 dephosphorylation can induce apoptosis (6), and inhibitor of MLCK can abrogate MLC2 phosphorylation, cell polarization, and migration (7). MLC2 is also involved in the activation of mid-G 1 phase cyclin D1 expression (8, 9). It has been reported that hyperphosphorylated MLC2 induces stress fiber formation and integrin clustering that link cell surface cytoskeletal proteins such as FAK to actin (10, 11). FAK is a member of the focal adhesions that mediates integrin-mediated signal transduction associated with a variety of cellular functions including cellular proliferation, migration, and adhesion (12). Downstream signaling pathways implicated in FAK signaling include the Jun N-termin...

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Critical Role of Peroxisome Proliferator-Activated Receptor γ on Anoikis and Invasion of Squamous Cell Carcinoma

Cited by 54 publications

References 37 publications

Activation of Peroxisome Proliferator-Activated Receptor-γ Decreases Pancreatic Cancer Cell Invasion through Modulation of the Plasminogen Activator System

Activation of Peroxisome Proliferator-Activated Receptor-γ Decreases Pancreatic Cancer Cell Invasion through Modulation of the Plasminogen Activator System

Expression of fatty acid binding protein 4 is involved in the cell growth of oral squamous cell carcinoma

MR-1 Modulates Proliferation and Migration of Human Hepatoma HepG2 Cells through Myosin Light Chains-2 (MLC2)/Focal Adhesion Kinase (FAK)/Akt Signaling Pathway

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