Next Article in Journal
Genomic Signature of Oral Squamous Cell Carcinomas from Non-Smoking Non-Drinking Patients
Next Article in Special Issue
Advanced Pediatric Diffuse Pontine Glioma Murine Models Pave the Way towards Precision Medicine
Previous Article in Journal
Granulocyte Colony Stimulating Factor Expression in Breast Cancer and Its Association with Carbonic Anhydrase IX and Immune Checkpoints
Previous Article in Special Issue
Pediatric Glioma: An Update of Diagnosis, Biology, and Treatment
Article

CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells

1
Neuroscience Institute Cavalieri Ottolenghi, 10043 Turin, Italy
2
Department of Neuroscience ‘Rita Levi Montalcini’, University of Turin, 10126 Turin, Italy
3
Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Felice Giangaspero
Cancers 2021, 13(5), 1028; https://doi.org/10.3390/cancers13051028
Received: 18 January 2021 / Revised: 17 February 2021 / Accepted: 24 February 2021 / Published: 1 March 2021
(This article belongs to the Special Issue Pediatric Brain Tumors)
Medulloblastoma (MB) is the most frequent brain tumor in children. The standard treatment consists in surgery, followed by radiotherapy and chemotherapy. These therapies are only partially effective, since many patients still die and those who survive suffer from neurological and endocrine disorders. Therefore, more effective therapies are needed. CENPE is a gene critical for normal proliferation and survival of neural progenitors. Since there is evidence that MB cells are very similar to neural progenitors, we hypothesized that CENPE could be an effective target for MB treatment. In MB cell lines, CENPE depletion induced defects in division and resulted in cell death. To consolidate CENPE as a target for MB treatment, we tested GSK923295, a specific inhibitor already in clinical trials for other cancer types. GSK923295 induced effects similar to CENPE depletion at low nM levels, supporting the idea that CENPE’s inhibition could be a viable strategy for MB treatment.
Medulloblastoma (MB) is the most frequent brain tumor in children. The standard treatment consists in surgery, followed by radiotherapy and chemotherapy. These therapies are only partially effective since many patients still die and those who survive suffer from neurological and endocrine disorders. Therefore, more effective therapies are needed. Primary microcephaly (MCPH) is a rare disorder caused by mutations in 25 different genes. Centromere-associated protein E (CENPE) heterozygous mutations cause the MCPH13 syndrome. As for other MCPH genes, CENPE is required for normal proliferation and survival of neural progenitors. Since there is evidence that MB shares many molecular features with neural progenitors, we hypothesized that CENPE could be an effective target for MB treatment. In ONS-76 and DAOY cells, CENPE knockdown induced mitotic defects and apoptosis. Moreover, CENPE depletion induced endogenous DNA damage accumulation, activating TP53 or TP73 as well as cell death signaling pathways. To consolidate CENPE as a target for MB treatment, we tested GSK923295, an allosteric inhibitor already in clinical trial for other cancer types. GSK923295, induced effects similar to CENPE depletion with higher penetrance, at low nM levels, suggesting that CENPE’s inhibition could be a therapeutic strategy for MB treatment. View Full-Text
Keywords: CENPE; microcephaly; DNA damage; childhood brain tumor; 53BP1; γH2AX; mitotic catastrophe CENPE; microcephaly; DNA damage; childhood brain tumor; 53BP1; γH2AX; mitotic catastrophe
Show Figures

Graphical abstract

MDPI and ACS Style

Iegiani, G.; Gai, M.; Di Cunto, F.; Pallavicini, G. CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells. Cancers 2021, 13, 1028. https://doi.org/10.3390/cancers13051028

AMA Style

Iegiani G, Gai M, Di Cunto F, Pallavicini G. CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells. Cancers. 2021; 13(5):1028. https://doi.org/10.3390/cancers13051028

Chicago/Turabian Style

Iegiani, Giorgia, Marta Gai, Ferdinando Di Cunto, and Gianmarco Pallavicini. 2021. "CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells" Cancers 13, no. 5: 1028. https://doi.org/10.3390/cancers13051028

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop