title: Tankyrase inhibition impairs directional migration and invasion of lung cancer cells by affecting microtubule dynamics and polarity signals.
abstract: BACKGROUND
  Tankyrases are poly(adenosine diphosphate)-ribose polymerases that contribute to biological processes as diverse as modulation of Wnt signaling, telomere maintenance, vesicle trafficking, and microtubule-dependent spindle pole assembly during mitosis. At interphase, polarized reshaping of the microtubule network fosters oriented cell migration. This is attained by association of adenomatous polyposis coli with the plus end of microtubules at the cortex of cell membrane protrusions and microtubule-based centrosome reorientation towards the migrating front.
  
  
  RESULTS
  Here we report a new function for tankyrases, namely, regulation of directional cell locomotion. Using a panel of lung cancer cell lines as a model system, we found that abrogation of tankyrase activity by two different, structurally unrelated small-molecule inhibitors (one introduced and characterized here for the first time) or by RNA interference-based genetic silencing weakened cell migration, invasion, and directional movement induced by the motogenic cytokine hepatocyte growth factor. Mechanistically, the anti-invasive outcome of tankyrase inhibition could be ascribed to sequential deterioration of the distinct events that govern cell directional sensing. In particular, tankyrase blockade negatively impacted (1) microtubule dynamic instability; (2) adenomatous polyposis coli plasma membrane targeting; and (3) centrosome reorientation.
  
  
  CONCLUSIONS
  Collectively, these findings uncover an unanticipated role for tankyrases in influencing at multiple levels the interphase dynamics of the microtubule network and the subcellular distribution of related polarity signals. These results encourage the further exploration of tankyrase inhibitors as therapeutic tools to oppose dissemination and metastasis of cancer cells.
authors.affiliation: Department of Oncology, University of Torino Medical School, 10060, Candiolo, Torino, Italy.|Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Strada Provinciale 142, km 3.95, 10060, Candiolo, Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lupo
authors.affiliation: Janssen Research & Development, a Division of Janssen Pharmaceutica NV, 2340, Beerse, Belgium.
authors.forename: Jorge
authors.initials: J
authors.lastname: Vialard
authors.affiliation: Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Strada Provinciale 142, km 3.95, 10060, Candiolo, Torino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sassi
authors.affiliation: Janssen Research & Development, a Division of Janssen-Cilag, 27106, Val-de-Reuil, Cedex, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Angibaud
authors.affiliation: Laboratory of Cell Migration, Candiolo Cancer Institute - FPO IRCCS, 10060, Candiolo, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Puliafito
authors.affiliation: Laboratory of Membrane Trafficking, Candiolo Cancer Institute - FPO IRCCS, 10060, Candiolo, Torino, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pupo
authors.affiliation: Department of Oncology, University of Torino Medical School, 10060, Candiolo, Torino, Italy.|Laboratory of Membrane Trafficking, Candiolo Cancer Institute - FPO IRCCS, 10060, Candiolo, Torino, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Lanzetti
authors.affiliation: Department of Oncology, University of Torino Medical School, 10060, Candiolo, Torino, Italy.|Experimental Clinical Molecular Oncology, Candiolo Cancer Institute - FPO IRCCS, 10060, Candiolo, Torino, Italy.
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.affiliation: Department of Oncology, University of Torino Medical School, 10060, Candiolo, Torino, Italy. andrea.bertotti@unito.it.|Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Strada Provinciale 142, km 3.95, 10060, Candiolo, Torino, Italy. andrea.bertotti@unito.it.|Istituto Nazionale di Biostrutture e Biosistemi, INBB, 00136, Rome, Italy. andrea.bertotti@unito.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.affiliation: Department of Oncology, University of Torino Medical School, 10060, Candiolo, Torino, Italy. livio.trusolino@unito.it.|Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute - FPO IRCCS, Strada Provinciale 142, km 3.95, 10060, Candiolo, Torino, Italy. livio.trusolino@unito.it.
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D034622:RNA Interference; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D038501:Tankyrases