Supplementary Video 1 from Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth
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posted on 2023-03-30, 21:08 authored by Renaud Prudent, Emilie Vassal-Stermann, Chi-Hung Nguyen, Catherine Pillet, Anne Martinez, Chloé Prunier, Caroline Barette, Emmanuelle Soleilhac, Odile Filhol, Anne Beghin, Glaucio Valdameri, Stéphane Honoré, Samia Aci-Sèche, David Grierson, Juliana Antonipillai, Rong Li, Attilio Di Pietro, Charles Dumontet, Diane Braguer, Jean-Claude Florent, Stefan Knapp, Ora Bernard, Laurence LafanechèreMOV file - 6MB, Effect of Pyr1 on microtubule dynamic instability - Time-lapse microscopy after 2 hours of incubation, on GFP-EB3 HeLa cells treated with DMSO (control), 5 muM, 10 muM or 25 muM Pyr1, as indicated. 4.Supplementary information
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ARTICLE 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.Usage metrics
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Cell SignalingProtein serine-threonine kinasesDrug Discovery TechnologiesScreening strategies (assays and chemical libraries)Drug ResistanceTransporter-based drug resistanceDrug TargetsProtein kinase & phosphatase drug targetsHematological CancersLeukemiasProgression, Invasion & MetastasisMigration and invasionSmall Molecule AgentsTubulin agents
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