Resistance is not futile: Surviving Eg5 inhibition

Dumas, Megan; Sturgill, Emma; Ohi, Ryoma

doi:10.1080/15384101.2016.1204864

Cited by 9 publications

(7 citation statements)

References 7 publications

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“…Indeed, several Kinesin-5 inhibitors were developed and their clinical trials conducted [122]. However, drug-resistant cell lines often emerged which hampered the clinical usage of these inhibitors [123][124][125].…”

Section: Towards Cancer Therapeuticsmentioning

confidence: 99%

“…To tackle this conundrum, a comprehensive understanding of in vivo Kinesin-5 functions and regulations, in addition to structural information on the interaction between Kinesin-5 and specific inhibitors [122,126], are necessary. As Kinesin-12 is essential for the survival of HeLa cells that become resistant to Kinein-5 inhibitors, the development of specific Kinesin-12 inhibitors would be important [106,108,125]. Given that destabilisation and/or the reduced dynamics of the microtubule rescues the lethality derived from Kinesin-5 inactivation [25,59], the combined treatment of Kinesin-5 inhibitors and microtubule stabilising reagents would be worth consideration.…”

Section: Towards Cancer Therapeuticsmentioning

confidence: 99%

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How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter

Yukawa

Teratani

Toda

2020

Cells

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The bipolar mitotic spindle drives accurate chromosome segregation by capturing the kinetochore and pulling each set of sister chromatids to the opposite poles. In this review, we describe recent findings on the multiple pathways leading to bipolar spindle formation in fission yeast and discuss these results from a broader perspective. The roles of three mitotic kinesins (Kinesin-5, Kinesin-6 and Kinesin-14) in spindle assembly are depicted, and how a group of microtubule-associated proteins, sister chromatid cohesion and the kinetochore collaborate with these motors is shown. We have paid special attention to the molecular pathways that render otherwise essential Kinesin-5 to become non-essential: how cells build bipolar mitotic spindles without the need for Kinesin-5 and where the alternate forces come from are considered. We highlight the force balance for bipolar spindle assembly and explain how outward and inward forces are generated by various ways, in which the proper fine-tuning of microtubule dynamics plays a crucial role. Overall, these new pathways have illuminated the remarkable plasticity and adaptability of spindle mechanics. Kinesin molecules are regarded as prospective targets for cancer chemotherapy and many specific inhibitors have been developed. However, several hurdles have arisen against their clinical implementation. This review provides insight into possible strategies to overcome these challenges.

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Section: Towards Cancer Therapeuticsmentioning

confidence: 99%

Section: Towards Cancer Therapeuticsmentioning

confidence: 99%

How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter

Yukawa

Teratani

Toda

2020

Cells

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“…The differential effects induced by these inhibitors implied multiple mitotic functions of Eg5 within the spindle. However, cultured cancer cells have been observed to develop resistance to Eg5 inhibitors, limiting clinical applications of these drugs 14 , 22 – 24 . To make improvements in cancer treatments targeting Eg5, a comprehensive understanding of the multiple functions of Eg5 and how these functions are modulated during spindle assembly is crucial.…”

Section: Introductionmentioning

confidence: 99%

HSP70 regulates Eg5 distribution within the mitotic spindle and modulates the cytotoxicity of Eg5 inhibitors

et al. 2020

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The heat shock protein 70 (HSP70) is a conserved molecular chaperone and proteostasis regulator that protects cells from pharmacological stress and promotes drug resistance in cancer cells. In this study, we found that HSP70 may promote resistance to anticancer drugs that target the mitotic kinesin, Eg5, which is essential for assembly and maintenance of the mitotic spindle and cell proliferation. Our data show that loss of HSP70 activity enhances Eg5 inhibitor-induced cytotoxicity and spindle abnormalities. Furthermore, HSP70 colocalizes with Eg5 in the mitotic spindle, and inhibition of HSP70 disrupts this colocalization. Inhibition or depletion of HSP70 also causes Eg5 to accumulate at the spindle pole, altering microtubule dynamics and leading to chromosome misalignment. Using ground state depletion microscopy followed by individual molecule return (GSDIM), we found that HSP70 inhibition reduces the size of Eg5 ensembles and prevents their localization to the inter-polar region of the spindle. In addition, bis(maleimido)hexane-mediated protein-protein crosslinking and proximity ligation assays revealed that HSP70 inhibition deregulates the interaction between Eg5 tetramers and TPX2 at the spindle pole, leading to their accumulation in high-molecular-weight complexes. Finally, we showed that the passive substrate-binding activity of HSP70 is required for appropriate Eg5 distribution and function. Together, our results show that HSP70 substratebinding activity may regulate proper assembly of Eg5 ensembles and Eg5-TPX2 complexes to modulate mitotic distribution/function of Eg5. Thus, HSP70 inhibition may sensitize cancer cells to Eg5 inhibitor-induced cytotoxicity.

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“…This phenotypic consequence is identical to what is observed in other organisms, including human cells when Kinesin-5 activity is inhibited (Sawin et al 1992; Kapoor et al 2000). Because its function is essential to cell proliferation, Kinesin-5 molecules have been targeted for the development of anticancer drugs (Wacker et al 2012; Ma et al 2014; Dumas et al 2016). However, at present, our knowledge on the physiology and regulation of Kinesin-5 motors is still too limited to draw a complete picture of their functions in vivo .…”

mentioning

confidence: 99%

Suppressor Analysis Uncovers That MAPs and Microtubule Dynamics Balance with the Cut7/Kinesin-5 Motor for Mitotic Spindle Assembly in Schizosaccharomyces pombe

Yukawa

Yamada

Toda

2019

G3 Genes|Genomes|Genetics

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The Kinesin-5 motor Cut7 in Schizosaccharomyces pombe plays essential roles in spindle pole separation, leading to the assembly of bipolar spindle. In many organisms, simultaneous inactivation of Kinesin-14s neutralizes Kinesin-5 deficiency. To uncover the molecular network that counteracts Kinesin-5, we have conducted a genetic screening for suppressors that rescue the cut7-22 temperature sensitive mutation, and identified 10 loci. Next generation sequencing analysis reveals that causative mutations are mapped in genes encoding α-, β-tubulins and the microtubule plus-end tracking protein Mal3/EB1, in addition to the components of the Pkl1/Kinesin-14 complex. Moreover, the deletion of various genes required for microtubule nucleation/polymerization also suppresses the cut7 mutant. Intriguingly, Klp2/Kinesin-14 levels on the spindles are significantly increased in cut7 mutants, whereas these increases are negated by suppressors, which may explain the suppression by these mutations/deletions. Consistent with this notion, mild overproduction of Klp2 in these double mutant cells confers temperature sensitivity. Surprisingly, treatment with a microtubule-destabilizing drug not only suppresses cut7 temperature sensitivity but also rescues the lethality resulting from the deletion of cut7, though a single klp2 deletion per se cannot compensate for the loss of Cut7. We propose that microtubule assembly and/or dynamics antagonize Cut7 functions, and that the orchestration between these two factors is crucial for bipolar spindle assembly.

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Resistance is not futile: Surviving Eg5 inhibition

Cited by 9 publications

References 7 publications

How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter

How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter

HSP70 regulates Eg5 distribution within the mitotic spindle and modulates the cytotoxicity of Eg5 inhibitors

Suppressor Analysis Uncovers That MAPs and Microtubule Dynamics Balance with the Cut7/Kinesin-5 Motor for Mitotic Spindle Assembly in Schizosaccharomyces pombe

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