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Publications (19)

  • [Show abstract] [Hide abstract] ABSTRACT: PIK3R1 (p85α regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1(R348∗) and a nearby mutation PIK3R1(L370fs), in contrast to wild-type and mutations in other regions of PIK3R1, confers an unexpected sensitivity to MEK and JNK inhibitors in vitro and in vivo. Consistent with the response to inhibitors, PIK3R1(R348∗) and PIK3R1(L370fs) unexpectedly increase JNK and ERK phosphorylation. Surprisingly, p85α R348(∗) and L370fs localize to the nucleus where the mutants provide a scaffold for multiple JNK pathway components facilitating nuclear JNK pathway activation. Our findings uncover an unexpected neomorphic role for PIK3R1(R348∗) and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors.
    Article · Oct 2014 · Cancer Cell
  • N Panupinthu · S Yu · D Zhang · [...] · G B Mills
    [Show abstract] [Hide abstract] ABSTRACT: The Y-box binding protein-1 (YB-1) transcription factor is associated with unfavorable clinical outcomes. However, the mechanisms underlying this association remain to be fully elucidated. We demonstrate that YB-1 phosphorylation, indicative of YB-1 activation, is a powerful marker of outcomes for ovarian cancer patients. In ovarian cancer, YB-1 phosphorylation is induced by activation of the lysophosphatidic acid (LPA) receptor (LPAR) via SRC-dependent transactivation of the epidermal growth factor receptor (EGFR) that is coupled to MAPK/p90 ribosomal S6 kinase (p90RSK), but not phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Activation of the LPAR/SRC/EGFR/MAPK/p90RSK/YB-1 axis leads to production of the EGFR ligand amphiregulin (AREG). AREG induces ongoing YB-1 phosphorylation as well as YB-1-dependent AREG expression, thus constituting an AREG/YB-1 self-reinforcing loop. Disruption of transactivation of the EGFR and the downstream self-reinforcing loop decreases invasiveness of ovarian cancer cells in vitro and limits ovarian cancer growth in xenograft models. These findings established the regulation and significance of YB-1 phosphorylation, therefore further exploration of this signaling axis as a therapeutic avenue in ovarian cancer is warranted.Oncogene advance online publication, 15 July 2013; doi:10.1038/onc.2013.259.
    Article · Jul 2013 · Oncogene
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    [Show abstract] [Hide abstract] ABSTRACT: Triple-negative breast cancers (TNBCs) are aggressive with no effective targeted therapies. A combined database analysis identified 32 inflammation-related genes differentially expressed in TNBCs, 10 proved critical for anchorage-independent growth. In TNBC cells a LPA-LPAR2-EZH2 NF-kappaB signaling cascade was essential for expression of IL-6, IL-8 and CXCL1. Concurrent inhibition of IL-6 and IL-8 expression dramatically inhibited colony formation and cell survival in vitro and stanched tumor engraftment and growth in vivo. A Cox multivariable analysis of patient specimens revealed that IL-6 and IL-8 expression predicted patient survival times. Together these findings offer a rationale for dual inhibition of IL-6/IL-8 signaling as a therapeutic strategy to improve outcomes for TNBC patients.
    Full-text Article · Apr 2013 · Cancer Research
  • Nattapon Panupinthu · Gordon B. Mills
    [Show abstract] [Hide abstract] ABSTRACT: This chapter contains sections titled: Linking Autotaxin (ATX) and Lysophosphatidic Acid (LPA) Receptors with Initiation and Progression of Cancer Implicating LPA in Tumorigenesis: Murine Models and Human Tumors LPA Signaling and Functions in Cancer Beyond the EDG Family of LPA Receptors Talking to the Neighbors: LPA Receptors in Context with Other Critical Players in Cancer Targeting the LPA Signaling Axis for Cancer Therapy Conclusions Acknowledgments References
    Chapter · Feb 2013
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    Kang Jin Jeong · Kyung Hwa Cho · Nattapon Panupinthu · [...] · Hoi Young Lee
    [Show abstract] [Hide abstract] ABSTRACT: Lysophosphatidic acid (LPA) augments proliferation and metastasis of various cancer cells. We recently identified a critical role of the Rho/ROCK pathway for LPA-induced proteolytic enzyme expression and cancer cell progression. In the present study, we elucidate the underlying mechanisms by which LPA induces Rho activation and subsequent cellular invasion, and the reversal of these effects by resveratrol. We observed that both Gi and G13 contribute to LPA-induced EGFR activation. The activated EGFR in turn initiates a Ras/Rho/ROCK signaling cascade, leading to proteolytic enzyme secretion. Further we provide evidence that resveratrol inhibits EGFR phosphorylation and subsequent activation of a Ras/Rho/ROCK signaling. Therefore, we demonstrate a mechanistic cascade of LPA activating EGFR through Gi and G13 thus inducing a Ras/Rho/ROCK signaling for proteolytic enzyme expression and ovarian cancer cell invasion, as well as interference of the cascade by resveratrol through blocking EGFR phosphorylation.
    Full-text Article · Oct 2012 · Molecular oncology
  • Stephen M Sims · Nattapon Panupinthu · Danielle M Lapierre · [...] · S Jeffrey Dixon
    [Show abstract] [Hide abstract] ABSTRACT: Osteoclasts (bone resorbing cells) and osteoblasts (bone forming cells) play essential roles in skeletal development, mineral homeostasis and bone remodeling. The actions of these two cell types are tightly coordinated, and imbalances in bone formation and resorption can result in disease states, such as osteoporosis. Lysophosphatidic acid (LPA) is a potent bioactive phospholipid that influences a number of cellular processes, including proliferation, survival and migration. LPA is also involved in wound healing and pathological conditions, such as tumor metastasis and autoimmune disorders. During trauma, activated platelets are likely a source of LPA in bone. Physiologically, osteoblasts themselves can also produce LPA, which in turn promotes osteogenesis. The capacity for local production of LPA, coupled with the proximity of osteoblasts and osteoclasts, leads to the intriguing possibility that LPA acts as a paracrine mediator of osteoblast-osteoclast signaling. Here we summarize emerging evidence that LPA enhances the differentiation of osteoclast precursors, and regulates the morphology, resorptive activity and survival of mature osteoclasts. These actions arise through stimulation of multiple LPA receptors and intracellular signaling pathways. Moreover, LPA is a potent mitogen implicated in promoting the metastasis of breast and ovarian tumors to bone. Thus, LPA released from osteoblasts is potentially an important autocrine and paracrine mediator - physiologically regulating skeletal development and remodeling, while contributing pathologically to metastatic bone disease. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
    Article · Aug 2012 · Biochimica et Biophysica Acta
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    Fa-Xing Yu · Bin Zhao · Nattapon Panupinthu · [...] · Kun-Liang Guan
    [Show abstract] [Hide abstract] ABSTRACT: The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR.
    Full-text Article · Aug 2012 · Cell
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    [Show abstract] [Hide abstract] ABSTRACT: Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipase D activity, which leads to generation of the growth-factor-like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy-resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4-tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues block ATX activity with K(i) values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates through a mixed-mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes. Analogues 22 and 30 b, the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers in vitro in a dose-dependent manner. The average terminal half-life for compound 22 is 10±5.4 h and it causes a long-lasting decrease in plasma LPA levels. Compounds 22 and 30 b significantly decrease lung metastasis of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment paradigm. The 4-substituted benzylphosphonic acids and 6-substituted naphthalen-2-ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX-LPA-LPAR axis both in vitro and in vivo.
    Full-text Article · May 2011 · ChemMedChem
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    S.Y. Park · K J Jeong · N Panupinthu · [...] · HY Lee
    [Show abstract] [Hide abstract] ABSTRACT: Lysophosphatidic acid (LPA), produced extracellularly by autotaxin (ATX), has diverse biological activities implicated in tumor initiation and progression, including increasing cell survival, angiogenesis, invasion and metastasis. ATX, LPA and the matrix metalloproteinase (MMP)-9 have all been implicated in hepatocellular carcinoma (HCC) invasion and metastasis. We, thus sought to determine whether ATX with subsequent LPA production and action, including induction of MMP-9 could provide a unifying mechanism. ATX transcripts and LPA receptor type 1 (LPA1) protein are elevated in HCC compared with normal tissues. Silencing or pharmacological inhibition of LPA1 significantly attenuated LPA-induced MMP-9 expression and HCC cell invasion. Further, reducing MMP-9 activity or expression significantly inhibits LPA-induced HCC cell invasion, demonstrating that MMP-9 is downstream of LPA1. Inhibition of phosphoinositide-3 kinase (PI3K) signaling or dominant-negative mutants of protein kinase Cδ and p38 mitogen-activated protein kinase (MAPK) abrogated LPA-induced MMP-9 expression and subsequent invasion. We thus demonstrate a mechanistic cascade of ATX-producing LPA with LPA activating LPA1 and inducing MMP-9 through coordinate activation of the PI3K and the p38 MPAK signaling cascades, providing novel biomarkers and potential therapeutic targets for HCC.
    Full-text Article · Nov 2010 · Oncogene
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    [Show abstract] [Hide abstract] ABSTRACT: Cyclic phosphatidic acid (CPA) is a naturally occurring analog of lysophosphatidic acid (LPA) in which the sn-2 hydroxy group forms a five-membered ring with the sn-3 phosphate. Here, we describe the synthesis of R-3-CCPA and S-3-CCPA along with their pharmacological properties as inhibitors of lysophospholipase D/autotaxin, agonists of the LPA(5) GPCR, and blockers of lung metastasis of B16-F10 melanoma cells in a C57BL/6 mouse model. S-3CCPA was significantly more efficacious in the activation of LPA(5) compared to the R-stereoisomer. In contrast, no stereoselective differences were found between the two isomers toward the inhibition of autotaxin or lung metastasis of B16-F10 melanoma cells in vivo. These results extend the potential utility of these compounds as potential lead compounds warranting evaluation as cancer therapeutics.
    Full-text Article · Oct 2010 · Bioorganic & medicinal chemistry letters
  • N Panupinthu · H.Y. Lee · G.B. Mills
    [Show abstract] [Hide abstract] ABSTRACT: Lysophosphatidic acid (LPA) is a potent lipid mediator that acts on a series of specific G protein-coupled receptors, leading to diverse biological actions. Lysophosphatidic acid induces cell proliferation, survival and migration, which are critically required for tumour formation and metastasis. This bioactive lipid is produced by the ectoenzyme lysophospholipase D or autotaxin (ATX), earlier known as an autocrine motility factor. The ATX-LPA signalling axis has emerged as an important player in many types of cancer. Indeed, aberrant expression of ATX and LPA receptors occurs during the development and progression of breast cancer. Importantly, expression of either ATX or LPA receptors in the mammary gland of transgenic mice is sufficient to induce the development of a high frequency of invasive and metastatic mammary cancers. The focus of research now turns to understanding the mechanisms by which ATX and LPA promote mammary tumourigenesis and metastasis. Targeting the ATX-LPA signalling axis for drug development may further improve outcomes in patients with breast cancer.
    Article · Mar 2010 · British Journal of Cancer
  • Shuying Liu · Mandi Murph · Nattapon Panupinthu · Gordon B Mills
    [Show abstract] [Hide abstract] ABSTRACT: Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) mediates a plethora of physiological and pathological activities via interactions with a series of high affinity G protein-coupled receptors (GPCR). Both LPA receptor family members and autotaxin (ATX/LysoPLD), the primary LPA-producing enzyme, are aberrantly expressed in many human breast cancers and several other cancer lineages. Using transgenic mice expressing either an LPA receptor or ATX, we recently demonstrated that the ATX-LPA receptor axis plays a causal role in breast tumorigenesis and cancer-related inflammation, further validating the ATX-LPA receptor axis as a rich therapeutic target in cancer.
    Article · Nov 2009 · Cell cycle (Georgetown, Tex.)
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    Matthew W. Grol · Nattapon Panupinthu · Jasminka Korcok · [...] · S Jeffrey Dixon
    [Show abstract] [Hide abstract] ABSTRACT: Nucleotides released from cells in response to mechanical stimulation or injury may serve as paracrine regulators of bone cell function. Extracellular nucleotides bind to multiple subtypes of P2 receptors on osteoblasts (the cells responsible for bone formation) and osteoclasts (cells with the unique ability to resorb mineralized tissues). Both cell lineages express the P2X7 receptor subtype. The skeletal phenotype of mice with targeted disruption of P2rx7 points to interesting roles for this receptor in the regulation of bone formation and resorption, as well as the response of the skeleton to mechanical stimulation. This paper reviews recent work on the expression of P2X7 receptors in bone, their associated signal transduction mechanisms and roles in regulating bone formation and resorption. Areas for future research in this field are also discussed.
    Full-text Article · Mar 2009 · Purinergic Signalling
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    Nattapon Panupinthu · Joseph T Rogers · Lin Zhao · [...] · S Jeffrey Dixon
    [Show abstract] [Hide abstract] ABSTRACT: Nucleotides are released from cells in response to mechanical stimuli and signal in an autocrine/paracrine manner through cell surface P2 receptors. P2rx7-/- mice exhibit diminished appositional growth of long bones and impaired responses to mechanical loading. We find that calvarial sutures are wider in P2rx7-/- mice. Functional P2X7 receptors are expressed on osteoblasts in situ and in vitro. Activation of P2X7 receptors by exogenous nucleotides stimulates expression of osteoblast markers and enhances mineralization in cultures of rat calvarial cells. Moreover, osteogenesis is suppressed in calvarial cell cultures from P2rx7-/- mice compared with the wild type. P2X7 receptors couple to production of the potent lipid mediators lysophosphatidic acid (LPA) and prostaglandin E2. Either an LPA receptor antagonist or cyclooxygenase (COX) inhibitors abolish the stimulatory effects of P2X7 receptor activation on osteogenesis. We conclude that P2X7 receptors enhance osteoblast function through a cell-autonomous mechanism. Furthermore, a novel signaling axis links P2X7 receptors to production of LPA and COX metabolites, which in turn stimulate osteogenesis.
    Full-text Article · Jun 2008 · The Journal of Cell Biology
  • Julie C Kudirka · Nattapon Panupinthu · Mark A Tesseyman · [...] · Suzanne M Bernier
    [Show abstract] [Hide abstract] ABSTRACT: Extracellular matrix influences cell behavior through receptors such as integrins and through transmission of mechanical forces. Nucleotides are released in response to mechanical stimuli and bind to P2 nucleotide receptors. As chondrocytes are subjected to frequent mechanical stimulation within a rich extracellular matrix, they are an excellent model for studying integration of signals induced by matrix and nucleotides. We investigated signaling of G protein-coupled P2Y receptors to MAPK/ERK and how this is influenced by matrix. Rat articular chondrocytes expressed transcripts for P2Y1, P2Y2, P2Y4, and P2Y6 receptors and responded to extracellular nucleotides by transient elevation of cytosolic calcium and MAPK/ERK phosphorylation. ERK1/2 activation was suppressed by the protein kinase C (PKC) inhibitors bisindolylmaleimide I and rottlerin, and by the phospholipase D inhibitor 1-butanol. Thus, nucleotides stimulate P2Y receptors to activate ERK1/2 through a mechanism dependent on PKC and phospholipase D. We next examined the involvement of integrins. Both an RGD-containing pentapeptide and a beta3 integrin blocking antibody, but not a beta1 integrin blocking antibody, abolished nucleotide-induced ERK1/2 phosphorylation. Moreover, chondrocytes adhering to fibronectin (which binds to beta1 and beta3 containing integrins in an RGD-dependent manner) displayed prolonged ERK1/2 signaling compared to cells grown on type I or II collagen (which bind to beta1-containing integrins in an RGD-independent manner). In conclusion, P2Y receptor signaling through ERK1/2 is gated selectively by matrix proteins. Thus, nucleotides released in response to mechanical stimulation will have differing effects on cell function due to changes in the composition of the extracellular matrix during development and disease.
    Article · Oct 2007 · Journal of Cellular Physiology
  • Nattapon Panupinthu · Lin Zhao · Fred Possmayer · [...] · S Jeffrey Dixon
    [Show abstract] [Hide abstract] ABSTRACT: Extracellular nucleotides, released in response to mechanical or inflammatory stimuli, signal through P2 receptors in many cell types, including osteoblasts. P2X7 receptors are ATP-gated cation channels that can induce formation of large membrane pores. Disruption of the gene encoding the P2X7 receptor leads to decreased periosteal bone formation and insensitivity of the skeleton to mechanical stimulation. Our purpose was to investigate signaling pathways coupled to P2X7 activation in osteoblasts. Live cell imaging showed that ATP or 2 ',3 '-O-(4-benzoylbenzoyl)-ATP (BzATP), but not UTP, UDP, or 2-methylthio-ADP, induced dynamic membrane blebbing in calvarial osteoblasts. Blebbing was observed in calvarial cells from wildtype but not P2X7 knock-out mice. P2X7 receptors coupled to activation of phospholipase D and A2, inhibition of which suppressed BzATP-induced blebbing. Activation of these phospholipases leads to production of lysophosphatidic acid (LPA). LPA caused dynamic blebbing in osteoblasts from both wild-type and P2X7 knock-out mice, similar to that induced by BzATP in wildtype cells. However, LPA-induced blebbing was more rapid in onset and was not affected by inhibition of phospholipase D or A2. Blockade or desensitization of LPA receptors suppressed blebbing in response to LPA and BzATP, without affecting P2X7-stimulated pore formation. Thus, LPA functions downstream of P2X7 receptors to induce membrane blebbing. Furthermore, inhibition of Rho-associated kinase abolished blebbing induced by both BzATP and LPA. In summary, we propose a novel signaling axis that links P2X7 receptors through phospholipases to production of LPA and activation of Rho-associated kinase. This pathway may contribute to P2X7-stimulated osteogenesis during skeletal development and mechanotransduction.
    Article · Mar 2007 · Journal of Biological Chemistry
  • N Panupinthu · F Possmayer · SM Sims · SJ Dixon
    Conference Paper · Oct 2004
  • S Jeffrey Dixon · Rongguo Yu · Nattapon Panupinthu · John X Wilson
    [Show abstract] [Hide abstract] ABSTRACT: Acidification of the extracellular fluid modulates neurotransmission and ischemic injury in brain. The purpose of the present study was to investigate the effects of purine and pyrimidine transmitters on acid efflux from brain astrocytes. Using RT-PCR, we detected transcripts for the following nucleotide receptors in rat primary astrocyte cultures: P2X1, P2X2, P2X3, P2X4, P2X6, P2X7, P2Y1, P2Y2, P2Y4, and P2Y6. Adenosine 5'-triphosphate (ATP) was found to rapidly induce a biphasic increase in acid efflux, monitored by microphysiometry, consisting of an initial transient and a sustained plateau. Compared with ATP, the P2Y agonist uridine 5'-triphosphate (UTP) induced a much smaller initial response but an equal plateau. The poorly hydrolyzable ATP analogue ATPgammaS caused the same initial response as did ATP, but a much smaller plateau, suggesting that the latter phase was due to extracellular degradation of nucleotides. The P2 receptor antagonist, suramin, blocked stimulation of acid efflux by ATP. Removal of extracellular glucose or elevation of extracellular K+ decreased the basal rate of acid efflux but not the stimulation induced by ATP. Inhibition of Na+/H+ exchange by cariporide suppressed the initial phase of ATP-stimulated acid efflux. The intracellular Ca2+ chelator bisaminophenoxyethane- tetraacetic acid (BAPTA) lowered basal acid efflux and abolished the initial phase of the response to ATP. In conclusion, ATP acts through P2 nucleotide receptors on astrocytes to stimulate the Ca2+ -dependent efflux of protons, mediated in part by activation of Na+/H+ exchange. The resulting acidification of the extracellular fluid may serve as an intercellular signal in brain.
    Article · Sep 2004 · Glia
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    [Show abstract] [Hide abstract] ABSTRACT: The P2X7 nucleotide receptor is an ATP-gated ion channel expressed widely in cells of hematopoietic origin. Our purpose was to explore the involvement of the P2X7 receptor in bone development and remodeling by characterizing the phenotype of mice genetically modified to disrupt the P2X7 receptor [knockout (KO)]. Femoral length did not differ between KO and wild-type (WT) littermates at 2 or 9 months of age, indicating that the P2X7 receptor does not regulate longitudinal bone growth. However, KO mice displayed significant reduction in total and cortical bone content and periosteal circumference in femurs, and reduced periosteal bone formation and increased trabecular bone resorption in tibias. Patch clamp recording confirmed expression of functional P2X7 receptors in osteoclasts from WT but not KO mice. Osteoclasts were present in vivo and formed in cultures of bone marrow from KO mice, indicating that this receptor is not essential for fusion of osteoclast precursors. Functional P2X7 receptors were also found in osteoblasts from WT but not KO mice, suggesting a direct role in bone formation. P2X7 receptor KO mice demonstrate a unique skeletal phenotype that involves deficient periosteal bone formation together with excessive trabecular bone resorption. Thus, the P2X7 receptor represents a novel therapeutic target for the management of skeletal disorders such as osteoporosis.
    Full-text Article · Aug 2003 · Molecular Endocrinology