The Aurora-A/TPX2 Axis Directs Spindle Orientation in Adherent Human Cells by Regulating NuMA and Microtubule Stability

Polverino, Federica; Naso, Francesco; Asteriti, Italia Anna; Palmerini, Valentina; Singh, Divya; Valente, Davide; Bird, Alexander W.; Rosa, Alessandro; Mapelli, Marina; Guarguaglini, Giulia

doi:10.1016/j.cub.2020.10.096

Cited by 33 publications

(24 citation statements)

References 46 publications

(46 reference statements)

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“…The Aurora kinase and TPX2 are co-overexpressed in several types of tumors and function as a complex [98]. The interaction between TPX2 and Aurora is essential for the proliferation of human cancerous cells [ 68 ]. TPX2 also protects Aurora from the degradation by the cdh1-activated anaphase-promoting complex/cyclosome (APC/C) proteasome’s activation [ 69 , 70 ].…”

Section: Discussionmentioning

confidence: 99%

TPX2 enhances the transcription factor activation of PXR and enhances the resistance of hepatocellular carcinoma cells to antitumor drugs

et al. 2023

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The pregnane X receptor (PXR) is an important regulator of hepatocellular carcinoma cellular resistance to antitumor drugs. Activation of PXR was modulated by the co-regulators. The target protein for the Xenopus plus end-directed kinesin-like protein (Xklp2) known as TPX2 that was previously considered as a tubulin regulator, also functions as the regulator of some transcription factors and pro-oncogenes in human malignances. However, the actions of TPX2 on PXR and HCC cells are still unclear. In the present study, our results demonstrate that the high expression of endogenous mRNA level of TPX2 not only correlated with the poor prognosis of advanced HCC patients who received sorafenib treatment but also with expression of PXR’s downstream genes, cyp3a4 and/or mdr-1. Results from luciferase and real-time polymerase chain reaction (qPCR) showed that TPX2 leads to enhancement of the transcription factor activation of PXR. Protein–protein interactions between PXR and TPX2 were identified using co-immunoprecipitation. Mechanically, overexpression of TPX2 led to enhancement of PXR recruitment to its downstream gene cyp3a4’s promoter region (the PXRE region) or enhancer region (the XREM region). Treatment of HCC cells with paclitaxel, a microtubule promoter, led to enhancement of the effects of TPX2, whereas vincristine, a microtubule depolymerizing agent caused a decrease in TPX2-associated effects. TPX2 was found to cause acceleration of the metabolism or clearance of sorafenib, a typical tyrosine kinase inhibitor (TKI) in HCC cells and in turn led to the resistance to sorafenib by HCC cells. By establishing novel actions of TXP2 on PXR in HCC cells, the results indicate that TPX2 could be considered a promising therapeutic target to enhance HCC cells sensitivity to antitumor drugs.

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Section: Discussionmentioning

confidence: 99%

TPX2 enhances the transcription factor activation of PXR and enhances the resistance of hepatocellular carcinoma cells to antitumor drugs

et al. 2023

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“…A conserved heterotrimeric complex, Gɑi‐LGN‐NuMA, is reportedly involved in regulating spindle orientation both in vivo and in vitro 26–28 . In this complex, LGN is an adaptor molecule of Gɑi.…”

Section: Conservative Heterotrimeric Complex Gɑi‐lgn‐numa Controls Sp...mentioning

confidence: 99%

“…A conserved heterotrimeric complex, Gɑi-LGN-NuMA, is reportedly involved in regulating spindle orientation both in vivo and in vitro. [26][27][28] In this complex, LGN is an adaptor molecule of Gɑi. It consists of three main domains: N-terminal TPR domain, central 'linker' domain and C-terminal GPR domain.…”

Section: Cons Ervative He Terotrimeric Comple X G ɑ I -Lg N -N Uma ...mentioning

confidence: 99%

Understanding the underlying mechanisms governing spindle orientation: How far are we from there?

Zhong

Gongye

Wang

et al. 2022

J Cellular Molecular Medi

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Proper spindle orientation is essential for cell fate determination and tissue morphogenesis. Recently, accumulating studies have elucidated several factors that regulate spindle orientation, including geometric, internal and external cues. Abnormality in these factors generally leads to defects in the physiological functions of various organs and the development of severe diseases. Herein, we first review models that are commonly used for studying spindle orientation. We then review a conservative heterotrimeric complex critically involved in spindle orientation regulation in different models. Finally, we summarize some cues that affect spindle orientation and explore whether we can establish a model that precisely elucidates the effects of spindle orientation without interfusing other spindle functions. We aim to summarize current models used in spindle orientation studies and discuss whether we can build a model that disturbs spindle orientation alone. This can substantially improve our understanding of how spindle orientation is regulated and provide insights to investigate this complex event.

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“…The serine/threonine kinase Aurora-A, essential for the cell division, is overexpressed in diverse tumors due to the somatic S155R mutation that prevents its interaction with its partner target protein for Xenopus kinesin-like protein 2 (TPX2) which keeps the stability of Aurora-A and helps the right orientation of Aurora-A in spindle microtubules (Bhardwaj & Purohit, 2020;Kufer et al, 2002;Polverino et al, 2020). Recently, Ala was found to re-build the native interaction between Aurora-A and TPX2, which would prevent the mislocalization of Aurora-A that is associated with oncogenic transformations, providing another kind of anticancer potential (Bhardwaj & Purohit, 2020).…”

Section: Antitumormentioning

confidence: 99%

Alantolactone: A sesquiterpene lactone with diverse pharmacological effects

et al. 2021

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Alantolactone (Ala) is a sesquiterpene lactone that can be isolated from many herbal plants belonging to Asteraceae. Besides the antimicrobial activities against bacteria, fungi and viruses, Ala has also demonstrated significant antiinflammatory effects in various models by inhibiting NF-κB and MAPKs to decrease the pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. The antitumor effects of Ala have been demonstrated in vitro and in vivo via inducing intrinsic apoptosis, oxidative stress, ER stress, cell cycle arrest and inhibiting autophagy and STAT3 phosphorylation, which are also involved in its combination or synergy with other antitumor drugs. Ala also has neuroprotective activity through attenuating oxidative stress and inflammation, besides its modulation of glucose and lipid metabolism. This review summarizes the recent advances of the pharmacological effects of Ala, including anti-inflammatory, antitumor, antimicrobial, neuroprotective activities, as well as the underlying mechanisms.Ala might be employed as a potential lead to develop drugs for multiple diseases.

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The Aurora-A/TPX2 Axis Directs Spindle Orientation in Adherent Human Cells by Regulating NuMA and Microtubule Stability

Cited by 33 publications

References 46 publications

TPX2 enhances the transcription factor activation of PXR and enhances the resistance of hepatocellular carcinoma cells to antitumor drugs

TPX2 enhances the transcription factor activation of PXR and enhances the resistance of hepatocellular carcinoma cells to antitumor drugs

Understanding the underlying mechanisms governing spindle orientation: How far are we from there?

Alantolactone: A sesquiterpene lactone with diverse pharmacological effects

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