Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth

Hepatocyte growth factor (HGF)/Met signaling controls cell migration, growth and differentiation in several embryonic organs and is implicated in human cancer. The physiologic mechanisms that attenuate Met signaling are not well understood. Here we report a mechanism by which mitogen-inducible gene 6 (Mig6; also called Gene 33 and receptor-associated late transducer) negatively regulates HGF/Met-induced cell migration. The effect is observed by Mig6 overexpression and is reversed by Mig6 small interfering RNA knock-down experiments; this indicates that endogenous Mig6 is part of a mechanism that inhibits Met signaling. Mig6 functions in cells of hepatic origin and in neurons, which suggests a role for Mig6 in different cell lineages. Mechanistically, Mig6 requires an intact Cdc42/Rac interactive binding site to exert its inhibitory action, which suggests that Mig6 acts, at least in part, distally from Met, possibly by inhibiting Rho-like GTPases. Because Mig6 also is induced by HGF stimulation, our results suggest that Mig6 is part of a negative feedback loop that attenuates Met functions in different contexts and cell types

Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures

International audienceThe development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by "RTK swapping" by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation

Combined drug action of 2-phenylimidazo[2,1-b]benzothiazole derivatives on cancer cells according to their oncogenic molecular signatures

The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by 'RTK swapping' by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation

Reparation du DNA dans les hepatocytes de rat adulte en culture pure et co-culture : mecanismes enzymatiques et expression d'oncogenes nucleaires

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Etude fonctionnelle du système HGF/Met au cours du développement normal et pathologique du système nerveux central

Les signaux participant au développement embryonnaire du système nerveux central peuvent à nouveau intervenir à l âge adulte, notamment lors d une pathologie. Nous avons analysé si le couple HGF/Met peut avoir de telles fonctions. Aussi, nous avons généré des souris porteuses d une mutation conditionnelle de Met spécifique du système nerveux. Nous avons montré que 1) dans le cerveau, Met participe à l établissement de l équilibre entre circuits excitateurs et inhibiteurs et 2) dans la moelle épinière, HGF/Met sont requis in vivo pour la survie d un sous-type de motoneurones. Nous avons aussi montré l intérêt du rôle neuroprotecteur de Met dans deux conditions pathologiques : un modèle murin de la sclérose latérale amyotrophique et dans la rétine après axotomie du nerf optique. Cette étude a montré que le système HGF/Met possède des propriétés trophiques spécifiques lors du développement des MNs et permet dans le cas d une neurodégénérescence de protéger les neurones contre l apoptose.Signals involved in development of the embryonic central nervous system can also play a role during adulthood, particularly in some pathologies. In order to analyze whether the HGF/Met system would have such functions, we generated met conditional mutant mice in which met is specifically removed in the nervous system. Using these mice, we have shown that 1) in the brain, Met is part of a system which controls the balance between excitatory and inhibitory circuits and 2) in the spinal cord, HGF/Met signaling is required in vivo for the survival of a specific subtype of motor neurons (MNs). We have also demonstrated the neuroprotective effect of HGF/Met in two pathological conditions such as the amyotrophic lateral sclerosis and after optic nerve axotomy. In conclusion, this work has allowed us to show the trophic properties of HGF/Met during normal development of specific subtypes of MNs, and its neuroprotective effect in neurodegenerative mouse modelsAIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Le système HGF/Met au cours du développement du système nerveux (réseau de signalisation impliqué dans la migration des neurones corticaux et caractérisation de nouvelles cibles géniques)

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

Imino-tetrahydro-benzothiazolederivatives as p53 inhibitors: discovery of a highly potent in vivo inhibitor and its action machanism.

International audienc

BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

International audienc