Different microtubule network alterations induced by pachymatismin, a new marine glycoprotein, on two prostatic cell lines.
Pachymatismin is a new cytostatic factor extracted from the marine sponge Pachymatisma johnstonii Bowerbank. To investigate the mechanism of action of pachymatismin, we studied its effects on two human prostate cell lines (DU145 and E4) of tumor origin. Immunocytochemistry demonstrated that the drug caused depolymerization of microtubules in DU145 cells, this effect being similar to that of estramustine, known to be a microtubule-depolymerizing agent. E4 cells, described to be resistant to the microtubule-depolymerizing agent estramustine, were also found resistant to pachymatismin. Pachymatismin at the same dose that destroys microtubule organization in DU145 cells is not able to induce microtubule depolymerization in E4 cells. Compared to the estramustine- and pachymatismin-sensitive DU145 cells, E4 cells revealed an increase of betaI+II, betaIII, betaIV isotypes as well as post-translational modifications of tubulin, such as polyglutamylation and acetylation. In addition, the level of tau protein was also enhanced in E4 cells compared to DU145 cells. The effects of pachymatismin were tested in vitro using calf brain microtubules. It was shown that the drug lowers the capacity of microtubules to reassemble in vitro. Interestingly, pachymatismin has been found to inhibit microtubule assembly less efficiently when the ratio of tau to tubulin is increased. Taken together, pachymastismin has been shown to induce in vivo microtubule depolymerization following binding to microtubule proteins. Changes in microtubule components such as tubulin isoforms or tau may be involved in a decrease of sensitivity to pachymatismin.
Sangrajrang
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Laboratoire de Pharmacologie, Institut de Génétique Moléculaire, Hôpital Saint-Louis, Institut de Génétique Moléculaire, 27 Rue Juliette Dodu, F-75010 Paris, France.
Zidane
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Berda
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Moré
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Calvo
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Fellous
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000494:pharmacology; D008870:Microtubules / Q000648:ultrastructure*; D011471:Prostatic Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000502:physiology
D000970:Antineoplastic Agents; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; C106743:pachymatismin protein, Pachymatisma johnstonii