title: Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma.
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.
authors: John Fulcher Neuro-oncology Laboratory, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK. n.syed@imperial.ac.uk
authors: N
authors: N
authors: Syed
authors: J
authors: J
authors: Langer
authors: K
authors: K
authors: Janczar
authors: P
authors: P
authors: Singh
authors: C
authors: C
authors: Lo Nigro
authors: L
authors: L
authors: Lattanzio
authors: H M
authors: HM
authors: Coley
authors: E
authors: E
authors: Hatzimichael
authors: J
authors: J
authors: Bomalaski
authors: P
authors: P
authors: Szlosarek
authors: M
authors: M
authors: Awad
authors: K
authors: K
authors: O'Neil
authors: F
authors: F
authors: Roncaroli
authors: T
authors: T
authors: Crook
mesh_terms: D017209:Apoptosis; D001120:Arginine / Q000378:metabolism; D001123:Argininosuccinate Lyase / Q000235:genetics / Q000378:metabolism*; D001124:Argininosuccinate Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016543:Central Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology; D002738:Chloroquine / Q000633:toxicity; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D057890:Epigenomics; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D034741:RNA, Small Interfering; D013267:Stilbenes; D011092:Polyethylene Glycols; D000077209:Decitabine; C004507:broparoestrol; D002738:Chloroquine; D001120:Arginine; D006867:Hydrolases; C512527:ADI PEG20; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase; D001374:Azacitidine