title: Pharmacological inhibition of LIM kinase stabilizes microtubules and inhibits neoplastic growth.
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.
authors: Institut Albert Bonniot, CRI INSERM/UJF U823, Team 3 Polarity, Development and Cancer, Rond-point de la Chantourne, La Tronche Cedex, France.
authors: Renaud
authors: R
authors: Prudent
authors: Emilie
authors: E
authors: Vassal-Stermann
authors: Chi-Hung
authors: CH
authors: Nguyen
authors: Catherine
authors: C
authors: Pillet
authors: Anne
authors: A
authors: Martinez
authors: Chloé
authors: C
authors: Prunier
authors: Caroline
authors: C
authors: Barette
authors: Emmanuelle
authors: E
authors: Soleilhac
authors: Odile
authors: O
authors: Filhol
authors: Anne
authors: A
authors: Beghin
authors: Glaucio
authors: G
authors: Valdameri
authors: Stéphane
authors: S
authors: Honoré
authors: Samia
authors: S
authors: Aci-Sèche
authors: David
authors: D
authors: Grierson
authors: Juliana
authors: J
authors: Antonipillai
authors: Rong
authors: R
authors: Li
authors: Attilio
authors: A
authors: Di Pietro
authors: Charles
authors: C
authors: Dumontet
authors: Diane
authors: D
authors: Braguer
authors: Jean-Claude
authors: JC
authors: Florent
authors: Stefan
authors: S
authors: Knapp
authors: Ora
authors: O
authors: Bernard
authors: Laurence
authors: L
authors: Lafanechère
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006367:HeLa Cells; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D055550:Protein Stability / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D014404:Tubulin; D050257:Tubulin Modulators; D054461:Lim Kinases