University of Surrey

Test tubes in the lab Research in the ATI Dance Research

Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma

Syed, N, Langer, J, Janczar, K, Singh, P, Roncaroli, F, Lo Nigro, C, Lattanzio, L, Coley, HM, Hatzimichael, E, Bomalaski, J, Szlosarek, P, Awad, M, O'Neil, K and Crook, T (2013) Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma Cell Death and Disease, 4 (1).

Full text not available from this repository.

Abstract

Arginine deprivation, either by nutritional starvation or exposure to ADI-PEG20, induces adaptive transcriptional upregulation of ASS1 and ASL in glioblastoma multiforme ex vivo cultures and cell lines. This adaptive transcriptional upregulation is blocked by neoplasia-specific CpG island methylation in either gene, causing arginine auxotrophy and cell death. In cells with methylated ASS1 or ASL CpG islands, ADI-PEG20 initially induces a protective autophagic response, but abrogation of this by chloroquine accelerates and potentiates cytotoxicity. Concomitant methylation in the CpG islands of both ASS1 and ASL, observed in a subset of cases, confers hypersensitivity to ADI-PEG20. Cancer stem cells positive for CD133 and methylation in the ASL CpG island retain sensitivity to ADI-PEG20. Our results show for the first time that epigenetic changes occur in both of the two key genes of arginine biosynthesis in human cancer and confer sensitivity to therapeutic arginine deprivation. We demonstrate that methylation status of the CpG islands, rather than expression levels per se of the genes, predicts sensitivity to arginine deprivation. Our results suggest a novel therapeutic strategy for this invariably fatal central nervous system neoplasm for which we have identified robust biomarkers and which overcomes the limitations to conventional chemotherapy imposed by the blood/ brain barrier. © 2013 Macmillan Publishers Limited All rights reserved.

Item Type: Article
Authors :
NameEmailORCID
Syed, NUNSPECIFIEDUNSPECIFIED
Langer, JUNSPECIFIEDUNSPECIFIED
Janczar, KUNSPECIFIEDUNSPECIFIED
Singh, PUNSPECIFIEDUNSPECIFIED
Roncaroli, FUNSPECIFIEDUNSPECIFIED
Lo Nigro, CUNSPECIFIEDUNSPECIFIED
Lattanzio, LUNSPECIFIEDUNSPECIFIED
Coley, HMh.coley@surrey.ac.ukUNSPECIFIED
Hatzimichael, EUNSPECIFIEDUNSPECIFIED
Bomalaski, JUNSPECIFIEDUNSPECIFIED
Szlosarek, PUNSPECIFIEDUNSPECIFIED
Awad, MUNSPECIFIEDUNSPECIFIED
O'Neil, KUNSPECIFIEDUNSPECIFIED
Crook, TUNSPECIFIEDUNSPECIFIED
Date : January 2013
Identification Number : https://doi.org/10.1038/cddis.2012.197
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:49
Last Modified : 17 May 2017 14:45
URI: http://epubs.surrey.ac.uk/id/eprint/825292

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year


Information about this web site

© The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.
+44 (0)1483 300800