Abstract
BackgroundMicrotubule drugs are effective anti-cancer agents, primarily due to their ability to induce mitotic arrest and subsequent cell death. However, some cancer cells are intrinsically resistant or acquire a resistance. Lack of apoptosis following mitotic arrest is thought to contribute to drug resistance that limits the efficacy of the microtubule-targeting anti-cancer drugs. Genetic or pharmacological agents that selectively facilitate the apoptosis of mitotic arrested cells present opportunities to strengthen the therapeutic efficacy.Methodology and Principal FindingsWe report a natural product Celastrol targets tubulin and facilitates mitotic cell death caused by microtubule drugs. First, in a small molecule screening effort, we identify Celastrol as an inhibitor of neutrophil chemotaxis. Subsequent time-lapse imaging analyses reveal that inhibition of microtubule-mediated cellular processes, including cell migration and mitotic chromosome alignment, is the earliest events affected by Celastrol. Disorganization, not depolymerization, of mitotic spindles appears responsible for mitotic defects. Celastrol directly affects the biochemical properties of tubulin heterodimer in vitro and reduces its protein level in vivo. At the cellular level, Celastrol induces a synergistic apoptosis when combined with conventional microtubule-targeting drugs and manifests an efficacy toward Taxol-resistant cancer cells. Finally, by time-lapse imaging and tracking of microtubule drug-treated cells, we show that Celastrol preferentially induces apoptosis of mitotic arrested cells in a caspase-dependent manner. This selective effect is not due to inhibition of general cell survival pathways or mitotic kinases that have been shown to enhance microtubule drug-induced cell death.Conclusions and SignificanceWe provide evidence for new cellular pathways that, when perturbed, selectively induce the apoptosis of mitotic arrested cancer cells, identifying a potential new strategy to enhance the therapeutic efficacy of conventional microtubule-targeting anti-cancer drugs.
Highlights
Microtubules (MTs), filamentous polymers of alpha- and betatubulin heterodimer, are essential cytoskeleton structures that control fundamental cellular processes, such as cell division, migration, intracellular transport and signaling
We provide evidence for new cellular pathways that, when perturbed, selectively induce the apoptosis of mitotic arrested cancer cells, identifying a potential new strategy to enhance the therapeutic efficacy of conventional microtubule-targeting anti-cancer drugs
We further demonstrated that this unique activity could be exploited to induce apoptosis of Taxol-resistant cancer cells, and to selectively facilitate the mitotic cell death of MT drug-arrested cancer cells
Summary
Microtubules (MTs), filamentous polymers of alpha- and betatubulin heterodimer, are essential cytoskeleton structures that control fundamental cellular processes, such as cell division, migration, intracellular transport and signaling (for review[1]). MTs are dynamic in nature and constantly undergo phases of shrinkage and re-growth, a process known as ‘dynamic instability’. This dynamic property underlies the vast majority of MT-based cellular processes [1]. The mitotic spindles are sensitive to various natural and synthetic MT drugs that impair their assembly and functions, leading to mitotic arrest and subsequent cell death. Due to this activity, MT drugs are most widely used to treat human cancers. Microtubule drugs are effective anti-cancer agents, primarily due to their ability to induce mitotic arrest and subsequent cell death. Genetic or pharmacological agents that selectively facilitate the apoptosis of mitotic arrested cells present opportunities to strengthen the therapeutic efficacy
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