ATP- and UTP-activated P2Y receptors differently regulate proliferation  of human lung epithelial tumor cells

Schäfer, Rainer; Sedehizade, Fariba; Welte, Tobias; Reiser, Georg

doi:10.1152/ajplung.00447.2002

Cited by 114 publications

(107 citation statements)

References 47 publications

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“…It is generally believed that intracellular Ca 2+ plays an important role in UTP-induced IL-6 production (28). We demonstrated that BAPTA-AM, an intracellular Ca 2+ chelator, suppressed UTP-induced ERK phosphorylation and IL-6 mRNA expression (Fig.…”

Section: +supporting

confidence: 53%

Contribution of Extracellular Signal-Regulated Kinase to UTP-Induced Interleukin-6 Biosynthesis in HaCaT Keratinocytes

Kobayashi

Ohkubo²,

Nakahata

2006

J Pharmacol Sci

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Abstract. UTP causes interleukin (IL)-6 production via mRNA expression through P2Y 2 / P2Y 4 receptors in human HaCaT keratinocytes. In the present study, we analyzed the mechanism of UTP-induced IL-6 production in these cells. UTP, an agonist of P2Y 2 / P2Y 4 receptors, induced phosphorylation of extracellular signal-regulated kinase (ERK) in a concentration-and timedependent manner. PD98059, a MEK (mitogen-activated protein kinase kinase) inhibitor, and BAPTA-AM [O,O'-bis(2-aminophenyl)ethyleneglycol-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester], an intracellular Ca 2+ chelator, reduced UTP-induced ERK phosphorylation and IL-6 mRNA expression. 2-APB [(2-aminoethoxy)diphenylborane], an inositol 1,4,5-trisphosphate (IP 3 )-receptor antagonist, inhibited UTP-induced IL-6 mRNA expression; and the action of A23187, a Ca 2+ ionophore, resembled the action of UTP. In contrast, protein kinase C (PKC) downregulation and pertussis toxin did not affect UTP-induced IL-6 mRNA expression, suggesting that PKC and G i are not involved in the UTP-induced IL-6 production. However, AG1478, an epidermal growth factor (EGF)-receptor inhibitor, partially decreased UTP-induced ERK phosphorylation and IL-6 expression. These results suggest that UTP-induced IL-6 production is in part mediated via phosphorylation of ERK through G q/ 11 / IP 3 / [Ca 2+] i and transactivation of the EGF receptor.

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Section: +supporting

confidence: 53%

Contribution of Extracellular Signal-Regulated Kinase to UTP-Induced Interleukin-6 Biosynthesis in HaCaT Keratinocytes

Kobayashi

Ohkubo²,

Nakahata

2006

J Pharmacol Sci

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“…It was reported that A549 cells express P2Y2 and P2Y6 purinergic receptors (23,24). We found in this study that ATP γ S markedly augments the migration of TGF β 1 -treated A549 cells (Fig.…”

Section: Discussionsupporting

confidence: 64%

“…Tumor cell-derived ATP has been suggested to play roles in tumor cell proliferation (19), intratumoral endothelial leakage (20), and adhesion of tumor cells to LECs (21). Although damaged cell-derived ATP may show favorable effects on anticancer immunity via P2RX7 receptors on dendritic cells (15), direct effects of endogenous ATP on A549 cell via P2Y receptors would be tumor-promoting, by stimulating cell proliferation (23) and migration (present study).…”

Section: Discussionmentioning

confidence: 74%

Transforming Growth Factor β1 Alters Calcium Mobilizing Properties and Endogenous ATP Release in A549 Cells: Possible Implications for Cell Migration

et al. 2010

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Abstract. We examined the effects of transforming growth factor β 1 (TGF β 1 ) on cellular functions in human lung cancer cell line A549. Treatment of A549 cells with 1 ng/ml TGF β 1 for more than 3 days altered their morphology from an epithelial cobblestone-like appearance to a fibroblastlike one, reduced the expression of E-cadherin mRNA and protein, and induced the formation of F-actin fibers. These hallmarks indicate that TGF β 1 induced the epithelial-mesenchymal transition in A549 cells. Migration of TGF β 1 -treated A549 cells, which was quantified by the wound-healing assay, was markedly accelerated by 3 μ M ATP γ S, a non-hydrolyzable ATP analogue. ATP γ Sinduced migration of TGF β 1 -treated A549 cells was reversed by the P2 antagonist suramin. In contrast, migration of control A549 cells was not altered by ATP γ S. TGF β 1 -treated A549 cells showed an augmentation of ATP-induced Ca 2+ transients, thapsigargin-induced Ca 2+ transients, and store-operated Ca 2+ entry compared with those in control cells. Basal level of the extracellular ATP concentration was significantly lower in TGF β 1 -treated A549 cells than in control cells. We conclude from these results that TGF β 1 augments ATP-induced Ca 2+ mobilization, which leads to the acceleration of migration, in A549 cells but, it markedly reduces endogenous ATP release. This implies that the actions of ATP would become a novel therapeutic target for inhibiting cancer cell migration.

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“…P2X7R expressing HEK cells show increased proliferation, reduced apoptosis and more developed vascular network in vivo with strong P2X7R positivity in several human cancers (Adinolfi et al 2012b). This is contradictory to previous reports indicating a proapoptotic effect of P2X7R in tumour cells (Greig et al 2003, Schafer et al 2003, Wang et al 2004b, White et al 2005, Shabbir & Burnstock 2009). Whether these differences are due to the potential preferential expression of P2X7R variants by different tumour cells is currently not known.…”

Section: P2x7r and Bone Cancercontrasting

confidence: 56%

P2X7 receptors: role in bone cell formation and function

Agrawal¹,

Gartland²

2015

Journal of Molecular Endocrinology

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The role of the P2X7 receptor (P2X7R) is being explored with intensive interest in the context of normal bone physiology, bone-related diseases and, to an extent, bone cancer. In this review, we cover the current understanding of P2X7R regulation of bone cell formation, function and survival. We will discuss how the P2X7R drives lineage commitment of undifferentiated bone cell progenitors, the vital role of P2X7R activation in bone mineralisation and its relatively unexplored role in osteocyte function. We also review how P2X7R activation is imperative for osteoclast formation and its role in bone resorption via orchestrating osteoclast apoptosis. Variations in the gene for the P2X7R (P2RX7) have implications for P2X7R-mediated processes and we review the relevance of these genetic variations in bone physiology. Finally, we highlight how targeting P2X7R may have therapeutic potential in bone disease and cancer. Purinergic signallingIn the last four decades, extensive investigations have led to the recognition of ATP from a 'molecular unit of energy' to an extracellular messenger molecule. ATP-sensitive purinoceptors, omnipresent in vertebrate tissues, are involved in a wide variety of physiological roles (Burnstock 2013) and their function has also been demonstrated in invertebrates (Verkhratsky & Burnstock 2014). While they traditionally act as cell surface sensors (Khakh & North 2006), their participation in signalling within the intracellular compartment in mammals (Qureshi et al. 2007, Kuehnel et al. 2009, Stokes & Surprenant 2009, Toulme et al. 2010) and even protozoans (Fountain et al. 2007, Ludlow et al. 2009, Sivaramakrishnan & Fountain 2012 has also been recognised.Purines (adenine, guanine and uridine) can act as signalling molecules in the form of their 5 0 -nucleotide triphosphates (such as ATP, GTP and UTP), diphosphates (ADP), monophosphate (AMP) or as a nucleoside (adenosine). They can activate one or more of the 19 receptors which are sorted into three classes: P1 (nucleoside) receptors; the metabotropic P2Y receptors and the ionotropic P2X, both of which are nucleotide triggered. Recently, a new family of purine receptors, AdeR or P0-receptors, responsive to adenine has been cloned from rodents (Bender et al. 2002, Gorzalka et al. 2005, von Kugelgen et al. 2008, Thimm et al. 2013, although the human homologue is yet to be identified. Structural and stoichiometrical evidence suggests that all P2X receptor (P2XR) subunits trimerise to form functional receptors (Nicke et al. 1998, Barrera et al. 2005, Mio et al. 2005, Kaczmarek-Hajek et al. 2012 with the subunits forming either homomultimers or heteromultimers depending on the subtypes (Burnstock 2007). Each unit comprises two transmembrane domains (TM1 and TM2) with an intervening large extracellular loop and cytoplasmic N-and C-termini, and the primary agonist of all homomeric and heteromeric P2XR is ATP. The current view holds that ligand binding causes reduction in the Journal of Molecular EndocrinologyReview A AGRAWAL and A GARTLAND P...

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ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells

Cited by 114 publications

References 47 publications

Contribution of Extracellular Signal-Regulated Kinase to UTP-Induced Interleukin-6 Biosynthesis in HaCaT Keratinocytes

Contribution of Extracellular Signal-Regulated Kinase to UTP-Induced Interleukin-6 Biosynthesis in HaCaT Keratinocytes

Transforming Growth Factor β1 Alters Calcium Mobilizing Properties and Endogenous ATP Release in A549 Cells: Possible Implications for Cell Migration

P2X7 receptors: role in bone cell formation and function

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