Targeting BUB3 in combination with paclitaxel inhibits proliferation of glioblastoma cells by enhancing cellular senescence

Patrícia Silva; Ana Nascimento; Olga Martinho; Rui Reis; Hassan  Bousbaa

doi:10.48797/sl.2022.11

Authors

Patrícia M. A. Silva UNIPRO - Oral Pathology and Rehabilitation Research Unit; TOXRUN - Toxicology Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal https://orcid.org/0000-0002-0694-7321
Ana V. Nascimento UNIPRO - Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal https://orcid.org/0000-0001-6828-1628
Olga Martinho Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, 4710-057 Braga, Portugal; Molecular Oncology Research Center, São Paulo 14784-400, Brazil https://orcid.org/0000-0002-3221-0403
Rui M. Reis Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, 4710-057 Braga, Portugal; Molecular Oncology Research Center, São Paulo 14784-400, Brazil https://orcid.org/0000-0002-9639-7940
Hassan Bousbaa UNIPRO - Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences (IUCS), CESPU, 4585-116 Gandra, Portugal; Interdisciplinary Center of Marine and Environmental Research (CIIMAR), University of Porto, 4450-208 Matosinhos, Portugal https://orcid.org/0000-0002-4006-5779

DOI:

https://doi.org/10.48797/sl.2022.11

Keywords:

glioblastoma, BUB3, paclitaxel, spindle assembly checkpoint, mitosis, senescence

Abstract

Glioblastoma (GBM) is the most common malignant primary brain tumor, with remarkably poor prognosis and survival rates. Existing treatments cannot cure GBM patients, and GBM recurrence remains a clinical bottleneck. To explore new GBM chemotherapeutic targets and new therapeutic strategies, the role of the spindle assembly checkpoint (SAC) protein BUB3 in GBM was investigated. We found BUB3 overexpression to be a common feature in GBM tissues. Moreover, BUB3 knockdown significantly inhibited proliferation of glioblastoma cells, and enhanced the antiproliferative activity of paclitaxel on these cells, through potentiation of multipolar spindles and SAC weakening. Interestingly, we showed that BUB3 downregulation exerts its antiproliferative activity mainly through induction of premature cellular senescence and, to a lesser extent, through apoptosis. Senescence phenotype, but not apoptosis, was highly potentiated in BUB3-depleted glioblastoma cells treated with clinically relevant doses of paclitaxel. Based on these observations, BUB3 inhibition combined with paclitaxel is suggested as a potentially effective strategy for the treatment of GBM. We propose BUB3 as a novel target and biomarker for GBM.

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