Novel antitubulin agents uncover new players in microtubule regulation and cell division in cancer
Cherry, Allison Elizabeth
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Glioblastoma multiforme (GBM) is a devastating and intractable type of cancer. Current antineoplastic drugs do not improve the median survival of patients diagnosed with GBM beyond 14-15 months in part because the blood-brain barrier is generally impermeable to many therapeutic agents. Drugs that target microtubules (MT) have shown remarkable efficacy in a variety of cancers, yet their use as GBM treatments has also been hindered by the scarcity of brain-penetrant MT-targeting compounds. We have discovered a new alkylindole compound, ST-11, that acts directly on MTs and rapidly attenuates their rate of assembly. Accordingly, ST-11 arrests GBM cells in prometaphase and triggers apoptosis. In vivo analyses reveal that unlike current antitubulin agents, ST-11 readily crosses the blood-brain barrier. Further investigation in a syngeneic orthotopic mouse model of GBM has revealed that ST-11 activates caspase-3 in tumors to reduce tumor volume without overt toxicity. Thus, ST-11 represents the first member of a new class of brain-penetrant antitubulin therapeutic agents. In addition to GBM, antitubulin agents are efficacious antineoplastic agents against a variety of cancers. A common drawback to their clinical use is the acquisition of drug resistance. The mechanisms governing cellular sensitivity to antitubulin compounds are complex. In particular, alterations in MT dynamics have been found to correlate with increased resistance to antitubulin compounds. Heterotrimeric G protein signaling has been implicated in the regulation of MT dynamics. However, research focusing on the effect of G proteins or heptahelical G protein coupled receptors (GPCRs) on sensitivity to antitubulin agents is lacking. Using multiple unbiased screens, biochemical analyses and live cell imaging techniques, we identified the orphan GPCR GPR124 as a novel coordinator of MT dynamics in cancer cells that regulates cellular sensitivity to MT-targeted agents, including ST-11. GPR124 associates with the MT plus end binding protein ch-TOG and increases its expression. Consequently, GPR124 increases spindle and interphase MT dynamics and the prevalence of lagging chromosomes during anaphase, which are evidence of increased chromosomal instability (CIN). High levels of CIN can lead to decreased tumor growth. Accordingly, overexpression of GPR124 significantly reduces the growth of U87MG xenograft tumors in vivo. Thus, our research supports a model in which GPR124 associates with ch-TOG to alter MT dynamics and increase lagging chromosomes that can lead to CIN and decreased tumor growth. Together, these studies describe a new brain-penetrant antitubulin agent and reveal novel MT regulatory components that affect antitubulin drug efficacy and tumor growth.
- Pharmacology