Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth |
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| Authors: | Prudent Renaud Vassal-Stermann Emilie Nguyen Chi-Hung Pillet Catherine Martinez Anne Prunier Chloé Barette Caroline Soleilhac Emmanuelle Filhol Odile Beghin Anne Valdameri Glaucio Honoré Stéphane Aci-Sèche Samia Grierson David Antonipillai Juliana Li Rong Di Pietro Attilio Dumontet Charles Braguer Diane Florent Jean-Claude Knapp Stefan Bernard Ora Lafanechère Laurence |
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| Affiliation: | Authors' Affiliations: Institut Albert Bonniot, CRI INSERM/UJF U823, Team 3 "Polarity, Development and Cancer", Rond-point de la Chantourne, La Tronche Cedex; CEA, DSV, iRTSV/CMBA; INSERM, U1036, CEA, iRTSV/BCI, Grenoble; Institut Curie, Centre de Recherche; CNRS, UMR 176, Paris; Institut Curie, Centre de Recherche, Batiment 112, Université Paris-Sud, Orsay; INSERM UMR 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Aix-Marseille Université, Marseille; Centre Commun de Quantimétrie, Faculté de Médecine Rockefeller; Equipe Labellisée Ligue 2009, Institut de Biologie et Chimie des Protéines FR 3302, BM2SI UMR 5086 CNRS/Université Lyon 1; INSERM 590, Faculté Rockefeller, Lyon, France and Université Lyon 1, ISPB, Lyon, France; St Vincent's Institute of Medical Research; The University of Melbourne, Department of Medicine, St Vincent's Hospital, Fitzroy, Victoria, Australia; and Department of Clinical Pharmacology, Oxford University, Oxford, United Kingdom. |
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| Abstract: | ![]()
The emergence of tumor resistance to conventional microtubule-targeting drugs restricts their clinical use. Using a cell-based assay that recognizes microtubule polymerization status to screen for chemicals that interact with regulators of microtubule dynamics, we identified Pyr1, a cell permeable inhibitor of LIM kinase, which is the enzyme that phosphorylates and inactivates the actin-depolymerizing factor cofilin. Pyr1 reversibly stabilized microtubules, blocked actin microfilament dynamics, inhibited cell motility in vitro and showed anticancer properties in vivo, in the absence of major side effects. Pyr1 inhibition of LIM kinase caused a microtubule-stabilizing effect, which was independent of any direct effects on the actin cytoskeleton. In addition, Pyr1 retained its activity in multidrug-resistant cancer cells that were resistant to conventional microtubule-targeting agents. Our findings suggest that LIM kinase functions as a signaling node that controls both actin and microtubule dynamics. LIM kinase may therefore represent a targetable enzyme for cancer treatment. Cancer Res; 72(17); 4429-39. ?2012 AACR. |
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