title: Pannexin1 drives multicellular aggregate compaction via a signaling cascade that remodels the actin cytoskeleton.
abstract: Pannexin 1 (Panx1) is a novel gap junction protein shown to have tumor-suppressive properties. To model its in vivo role in the intratumor biomechanical environment, we investigated whether Panx1 channels modulate the dynamic assembly of multicellular C6 glioma aggregates. Treatment with carbenoxolone and probenecid, which directly and specifically block Panx1 channels, respectively, showed that Panx1 is involved in accelerating aggregate assembly. Experiments further showed that exogenous ATP can reverse the inhibitive effects of carbenoxolone and that aggregate compaction is sensitive to the purinergic antagonist suramin. With a close examination of the F-actin microfilament network, these findings show that Panx1 channels act as conduits for ATP release that stimulate the P(2)X(7) purinergic receptor pathway, in turn up-regulating actomyosin function. Using a unique three-dimensional scaffold-free method to quantify multicellular interactions, this study shows that Panx1 is intimately involved in regulating intercellular biomechanical interactions pivotal in the progression of cancer.
authors.affiliation: Department of Molecular Pharmacology, Physiology, and Biotechnology, Center for Biomedical Engineering, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Bao
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lai
authors.forename: Christian C
authors.initials: CC
authors.lastname: Naus
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Morgan
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D000205:Actomyosin / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D002229:Carbenoxolone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004336:Drug Antagonism; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011339:Probenecid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014528:Uricosuric Agents / Q000494:pharmacology
chemical_list: D000897:Anti-Ulcer Agents; D017630:Connexins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D058486:Receptors, Purinergic P2X7; D014528:Uricosuric Agents; D000255:Adenosine Triphosphate; D000205:Actomyosin; D002229:Carbenoxolone; D011339:Probenecid