Natural product Celastrol destabilizes tubulin heterodimer and facilitates mitotic cell death triggered by microtubule-targeting anti-cancer drugs.
BACKGROUND
Microtubule 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.


RESULTS
We 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
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.
Jo
Hakryul
H
Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts, United States of America.
Loison
Fabien
F
Hattori
Hidenori
H
Silberstein
Leslie E
LE
Yu
Hongtao
H
Luo
Hongbo R
HR
D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001688:Biological Products / Q000627:therapeutic use; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis; D009504:Neutrophils / Q000166:cytology*; D053978:Pentacyclic Triterpenes; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D014404:Tubulin / Q000737:chemistry* / Q000187:drug effects
D000970:Antineoplastic Agents; D001688:Biological Products; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D014404:Tubulin; C050414:celastrol