N-terminus-modified Hec1 suppresses tumour growth by interfering with kinetochore-microtubule dynamics
| العنوان: | N-terminus-modified Hec1 suppresses tumour growth by interfering with kinetochore-microtubule dynamics |
|---|---|
| المؤلفون: | Augusto Orlandi, M Fiore, Jessica Lenzi, Marianna Desideri, Pierangela Totta, Daniela Passeri, Helder Maiato, Marin Barisic, F. Degrassi, Dd Bufalo, M Orticello, Alessandro Rosa |
| المساهمون: | Orticello, M, Fiore, M, Totta, Pierangela, Desideri, M, Barisic, M, Passeri, D, Lenzi, J, Rosa, A, Orlandi, A, Maiato, H, Bufalo, Dd, Degrassi, F. |
| المصدر: | Oncogene (Basingstoke) 34 (2015): 3325–3335. doi:10.1038/onc.2014.265doi info:cnr-pdr/source/autori:Orticello, Michela; Fiore, Mario; Totta, Pierangela; Desideri, Marianna; Barisic, Marin; Passeri, Daniela; Lenzi, Jessica; Rosa, Alessandro; Orlandi, Augusto; Maiato, Hélder; Del Bufalo, Donatella; Degrassi, Francesca/titolo:N-terminus-modified Hec1 suppresses tumour growth by interfering with kinetochore-microtubule dynamics/doi:10.1038%2Fonc.2014.265doi:/rivista:Oncogene (Basingstoke)/anno:2015/pagina_da:3325/pagina_a:3335/intervallo_pagine:3325–3335/volume:34 |
| بيانات النشر: | Macmillan, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Male, Cancer Research, Settore MED/06 - Oncologia Medica, Recombinant Fusion Proteins, chromosome segregation, Mitosis, Apoptosis, Biology, Cell Transformation, Microtubules, in-vivo, Kinetochore microtubule, Mice, checkpoint, expression, Genetics, Animals, Humans, microtubule dynamics, Spindle Poles, gene delivery, Kinetochores, mitotic catastrophe, Molecular Biology, Mitotic catastrophe, Cell Proliferation, cancer cell, Cell Transformation, Neoplastic, HeLa Cells, Nuclear Proteins, Tumor Suppressor Proteins, Neoplastic, Cell growth, mitotic progression, kinetochore-microtubule attachment, Cell cycle, Cell biology, Cytoskeletal Proteins, protein, instability, Cell killing, Cancer cell, Highly expressed in cancer protein 1, Multipolar spindles, anti-cancer therapy |
| الوصف: | Mitotic proteins are attractive targets to develop molecular cancer therapeutics due to the intimate interdependence between cell proliferation and mitosis. In this work, we have explored the therapeutic potential of the kinetochore (KT) protein Hec1 (Highly Expressed in Cancer protein 1) as a molecular target to produce massive chromosome missegregation and cell death in cancer cells. Hec1 is a constituent of the Ndc80 complex, which mediates KT-microtubule (MT) attachments at mitosis and is upregulated in various cancer types. We expressed Hec1 fused with enhanced green fluorescent protein (EGFP) at its N-terminus MT-interaction domain in HeLa cells and showed that expression of this modified Hec1, which localized at KTs, blocked cell proliferation and promoted apoptosis in tumour cells. EGFP-Hec1 was extremely potent in tumour cell killing and more efficient than siRNA-induced Hec1 depletion. In striking contrast, normal cells showed no apparent cell proliferation defects or cell death following EGFP-Hec1 expression. Live-cell imaging demonstrated that cancer cell death was associated with massive chromosome missegregation within multipolar spindles after a prolonged mitotic arrest. Moreover, EGFP-Hec1 expression was found to increase KT-MT attachment stability, providing a molecular explanation for the abnormal spindle architecture and the cytotoxic activity of this modified protein. Consistent with cell culture data, EGFP-Hec1 expression was found to strongly inhibit tumour growth in a mouse xenograft model by disrupting mitosis and inducing multipolar spindles. Taken together, these findings demonstrate that stimulation of massive chromosome segregation defects can be used as an anti-cancer strategy through the activation of mitotic catastrophe after a multipolar mitosis. Importantly, this study represents a clear proof of concept that targeting KT proteins required for proper KT-MT attachment dynamics constitutes a powerful approach in cancer therapy.Oncogene advance online publication, 18 August 2014; doi:10.1038/onc.2014.265. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a99d5e5d5e98e5b8f1613e86f07c6e66 http://hdl.handle.net/11573/602782 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a99d5e5d5e98e5b8f1613e86f07c6e66 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |