GTP-tubulin loves microtubule plus ends but marries the minus ends

Wordeman, Linda

doi:10.1083/jcb.201908039

Cited by 3 publications

(2 citation statements)

References 10 publications

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“…Dimers of α-tubulin and β-tubulin form 13 protofilaments that roll into a tubule, which are templated by the γ-tubulin ring complex 3 , 4 . GTP-bound dimers at the plus end promote microtubule growth, while the loss of this cap favors catastrophe 4 – 6 . During catastrophe the protofilaments adopt a curved state and bend away from the lumen 7 , 8 .…”

Section: Introductionmentioning

confidence: 99%

Characterization of a recently synthesized microtubule-targeting compound that disrupts mitotic spindle poles in human cells

Jaunky

Larocque

Husser

et al. 2021

Sci Rep

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We reveal the effects of a new microtubule-destabilizing compound in human cells. C75 has a core thienoisoquinoline scaffold with several functional groups amenable to modification. Previously we found that sub micromolar concentrations of C75 caused cytotoxicity. We also found that C75 inhibited microtubule polymerization and competed with colchicine for tubulin-binding in vitro. However, here we found that the two compounds synergized suggesting differences in their mechanism of action. Indeed, live imaging revealed that C75 causes different spindle phenotypes compared to colchicine. Spindles remained bipolar and collapsed after colchicine treatment, while C75 caused bipolar spindles to become multipolar. Importantly, microtubules rapidly disappeared after C75-treatment, but then grew back unevenly and from multiple poles. The C75 spindle phenotype is reminiscent of phenotypes caused by depletion of ch-TOG, a microtubule polymerase, suggesting that C75 blocks microtubule polymerization in metaphase cells. C75 also caused an increase in the number of spindle poles in paclitaxel-treated cells, and combining low amounts of C75 and paclitaxel caused greater regression of multicellular tumour spheroids compared to each compound on their own. These findings warrant further exploration of C75’s anti-cancer potential.

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Section: Introductionmentioning

confidence: 99%

Characterization of a recently synthesized microtubule-targeting compound that disrupts mitotic spindle poles in human cells

Jaunky

Larocque

Husser

et al. 2021

Sci Rep

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show abstract

“…Dimers of a-tubulin and b-tubulin form 13 protofilaments that roll into a tubule, which are templated by the g-tubulin ring complex (g-TURC; Oakley et al 2015;Martin and Akhmanova 2018). GTP-binding and hydrolysis influences microtubule structure and can promote growth or catastrophe (Wordeman 2019;Martin and Akhmanova 2018;Brouhard and Rice 2018). Straightening of the protofilament plus-ends are crucial for microtubule stability and growth.…”

Section: Introductionmentioning

confidence: 99%

A novel compound that disrupts mitotic spindle poles in human cells

Jaunky

Husser

Larocque

et al. 2020

Preprint

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We characterize the mechanism of action of a new microtubule-targeting compound in cells. Microtubule-targeting drugs are used as successful anti-cancer therapies. We synthesized a family of compounds that share a common scaffold and have several functional groups amenable to modifications. We found that one of the active derivatives, C75, reduces cell viability and prevents microtubule polymerization in vitro. In this study, we explore the phenotypes caused by C75 in cells. It causes mitotic arrest and spindle phenotypes in several cancer cell lines in the nanomolar range. C75 can bind to the Colchicine-pocket on tubulin in vitro, but causes different effects on microtubules in cells. While Colchicine causes a decrease in microtubules and spindle pole collapse without re-growth, similar concentrations of C75 cause a rapid loss of microtubules and spindle pole fragmentation followed by microtubule re-growth to form multipolar spindles. In addition, C75 and Colchicine synergize for reduced viability and spindle phenotypes. Importantly, the phenotypes caused by C75 are similar to those caused by the depletion of ch-TOG, a microtubule polymerase, and tubulin and ch-TOG are displaced and oscillate in C75-treated cells. This suggests that C75 causes microtubule depolymerization in cells either directly or indirectly via inhibiting ch-TOG. This unique effect of C75 on microtubules warrants further exploration of its anti-cancer potential.

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Microtubules and Cell Division: Potential Pharmacological Targets in Cancer Therapy

Rathinasamy

Sebastian

2023

CDT

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Microtubules are a well-known target in cancer chemotherapy because of their critical role in cell division. Chromosome segregation during mitosis depends on the establishment of the mitotic spindle apparatus through microtubule dynamics. The disruption of microtubule dynamics through the stabilization or destabilization of microtubules results in the mitotic arrest of the cells. Microtubule-targeted drugs, which interfere with microtubule dynamics, inhibit the growth of cells at the mitotic phase and induce apoptotic cell death. The principle of microtubule-targeted drugs is to arrest the cells at mitosis and reduce their growth because cancer is a disease of unchecked cell proliferation. Many anti-microtubule agents produce significant inhibition of cancer cell growth and are widely used as chemotherapeutic drugs for the treatment of cancer. The drugs that interact with microtubules generally bind at one of the three sites vinblastine site, taxol site, or colchicine site. Colchicine binds to the interface of tubulin heterodimer and induces the depolymerization of microtubules. The colchicine binding site on microtubules is a much sought-after target in the history of anti-microtubule drug discovery. Many colchicine-binding site inhibitors have been discovered, but their use in the treatment of cancer is limited due to their dose-limiting toxicity and resistance in humans. Combination therapy can be a new treatment strategy to overcome these drawbacks of currently available microtubule-targeted anticancer drugs. This review discusses the significance of microtubules as a potential pharmacological target for cancer and stresses the necessity of finding new microtubule inhibitors to fight the disease.

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GTP-tubulin loves microtubule plus ends but marries the minus ends

Cited by 3 publications

References 10 publications

Characterization of a recently synthesized microtubule-targeting compound that disrupts mitotic spindle poles in human cells

Characterization of a recently synthesized microtubule-targeting compound that disrupts mitotic spindle poles in human cells

A novel compound that disrupts mitotic spindle poles in human cells

Microtubules and Cell Division: Potential Pharmacological Targets in Cancer Therapy

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