Effects of stathmin inhibition on the mitotic spindle.

Stathmin is a major cytosolic phosphoprotein that plays an important role in the regulation of microtubule dynamics during cell cycle progression. It has recently been proposed that the major function of stathmin is to promote depolymerization of the microtubules that make up the mitotic spindle. In this report, we tested the prediction that a deficiency in stathmin expression would result in constitutive stabilization of microtubules and lead to abnormalities in the organization of the mitotic spindle. Our studies demonstrate that antisense inhibition of stathmin expression in K562 erythroleukemic cells results in increased ratio of polymerized to depolymerized tubulin. These changes are associated with phenotypic abnormalities of the mitotic spindle and difficulty in completing mitosis. These studies also showed that inhibition of stathmin expression results in increased susceptibility of K562 leukemic cells to the pharmacological agents, like taxol, which are known to stabilize the mitotic spindle. In contrast, stathmin inhibition results in decreased sensitivity to vinblastine, an agent that destabilizes the mitotic spindle. Thus, our experimental findings are supportive of the model that stathmin is a microtubule-destabilizing factor that plays an important role in the regulation of the mitotic spindle. We also suggest a potential therapeutic approach for cancer based on the combination of stathmin inhibition with pharmacologic agents that stabilize the mitotic spindle.