Stéphane Honoré – Microtubule dynamic instability : implication in Oncopharmacology

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Date(s) - 25 juin 2013

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MTs are governed by an intrinsic property involving repetitive spurts of shortening from their plus ends, followed by periods of polymerisation. This non-equilibrium behaviour called microtubule dynamic instability is based on the binding and hydrolysis of GTP at the nucleotide exchangeable site (E-site) in ?eta tubulin. Only dimers that have GTP in their E-site can polymerize. Then, this nucleotide is hydrolyzed and becomes non-exchangeable. The GTP cap model proposes that the GDP-tubulin core of MT is stabilized at the plus end by a layer of GTP-tubulin subunits that may act to maintain association between protofilaments. When this cap is stochastically lost, the protofilaments peel outward and the MT rapidly depolymerizes. Although both MT ends can either grow or shorten, the changes in length at the plus end are much greater than at the minus end. In cells, MT dynamics are regulated both spatially and temporally in cells by an impressive number of binding proteins. EB1, a Microtubule plus-end tracking protein (+TIPs) play an essential role in regulating microtubule dynamics and in conferring molecular recognition of the microtubule end which is crucial for many microtubule functions. Microtubule dynamics is an essential and indispensable property of microtubules. Requirement of dynamic MT is evident most notably during assembly of bipolar spindle and segregation of duplicated chromosomes in mitosis. During interphase, microtubule dynamics is also essential for maintaining cell shape and for controlling cell polarity and migration. Mechanism of action of anti-microtubule drugs MT dynamics is the target for a large and chemically diverse group of molecules called MTDs. The effectiveness of MTDs has been validated by the successful use of several Vinca alkaloids and taxanes for the treatment of a wide variety of human cancers. MTDs exert their inhibitory effects on cancer cell proliferation primarily by blocking mitosis, which requires a finely regulated control of MT dynamics. MTDs are therefore referred as anti-mitotic drugs. At cytotoxic concentrations, MTDs potently suppress MT dynamics. This occurs through several ways, depending on cell types, on the tubulin binding site (i.e. colchicine, Vinca alkaloid or paclitaxel binding site) but also on molecules. The anti-cancer effect of MTDs could also involve the high potency of these drugs to inhibit cell migration, a crucial cellular process controlling neo-angiogenesis, tumor cell invasion and metastasis. Suppression of interphase MT dynamics may thus represent the main mechanism of anti-migratory action of MTDs. However, such anti-migratory effect occurs simultaneously of the cytotoxic effect. It is thus of poor advantage in cancer treatment since these drugs are usually administered to patients at maximal tolerated dose every 1 to 3 weeks and that the anti-migratory action only occurs during the treatment period. Surviving tumor or endothelial cells may thus continue to migrate during the long drug-free episodes. The concept of anti-migratory action of MTDs at infracytotoxic concentrations was generalized to almost all MTDs and a wide variety of cell types including tumor and endothelial cells. Such mechanism involves an inhibition on EB1 accumulation at microtubule plus end as well as posttranslational modification of the protein.