Pharmacological inhibition of LIM Kinase stabilizes microtubules and inhibits neoplastic growth

Renaud Prudent (1) , Emilie Vassal-Stermann (2) , Chi-Hung Nguyen , Catherine Pillet (3) , Anne Martinez , Chloé Prunier (4) , Caroline Barette (5, 6) , Emmanuelle Soleilhac (7) , Odile Filhol (8) , Anne Beghin (9) , Glaucio Valdameri (10) , Stéphane Honoré (11) , Samia Aci-Sèche (12) , David S. Grierson (13) , Julia Antonipillai , Ron Li , Charles Dumontet (14) , Diane Braguer (15) , Jean-Claude Florent (16) , Stefan Knapp (17) , Ora Bernard , Laurence Lafanechère (18)

1 LAPM - Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble]
2 IBS - UMR 5075 - Institut de biologie structurale
3 BGE - UMR S1038 - Laboratoire de Biologie à Grande Échelle
4 Institut Albert Bonniot
5 GPMS / CMBA - Groupe Plateforme et Moyens Scientifiques et techniques communs / Centre de Criblage pour Molécules Bio-Actives
6 GenChem - Genetics and Chemogenomics
7 CEA Grenoble/DSV
8 Transduction du signal : signalisation calcium, phosphorylation et inflammation
9 Division Matériaux et Structures de Chaussées
10 BMSSI - Bases moléculaires et structurales des systèmes infectieux
11 TIMONE - Hôpital de la Timone [CHU - APHM]
12 CBM - Centre de biophysique moléculaire
13 CSVB - Conception, synthèse et vectorisation de biomolécules
14 UCBL - Université Claude Bernard Lyon 1
15 CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
16 CDC - Compartimentation et dynamique cellulaires
17 Nuffield Department of Clinical Medicine [Oxford]
18 INSERM U823 - Institut d'oncologie/développement Albert Bonniot de Grenoble

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 microtubul-estabilizing 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

Domaines: Biologie cellulaire; Cancer

Renaud Prudent, Emilie Vassal-Stermann, Chi-Hung Nguyen, Catherine Pillet, Anne Martinez, et al.. Pharmacological inhibition of LIM Kinase stabilizes microtubules and inhibits neoplastic growth. Cancer Research, 2012, 72 (17), pp.4429-4439. ⟨10.1158/0008-5472.CAN-11-3342⟩. ⟨hal-02348076⟩