title: Growth and DNA damage-inducible transcription factor 153 mediates apoptosis in response to fenretinide but not synergy between fenretinide and chemotherapeutic drugs in neuroblastoma.
abstract: Fenretinide induces apoptosis of neuroblastoma cells in vitro and interacts synergistically with the chemotherapeutic drugs cisplatin and etoposide. The stress-inducible transcription factor known as growth and DNA damage (GADD)-inducible transcription factor 153 is induced in response to fenretinide and in other cell types modulates apoptosis via pro- and antiapoptotic members of the BCL2 family. Because BCL2-family proteins are important in apoptosis induced by chemotherapeutic drugs, GADD153 may be a key mediator of synergy between fenretinide and chemotherapeutic drugs. To investigate this, GADD153 cDNA in sense and antisense orientations was stably transfected into SH-SY5Y neuroblastoma cells using a tetracycline-inducible vector. Increased expression of GADD153 raised the background level of apoptosis and increased apoptosis induced by fenretinide or the chemotherapeutic drugs cisplatin and etoposide. However, there was no increase in synergy between fenretinide and chemotherapeutic drugs. Conversely, expression of antisense-GADD153 virtually abolished the induction of apoptosis in response to fenretinide but overall had no significant effect on apoptosis induced by chemotherapeutic drugs. The effect of antisense-GADD153 on synergy between chemotherapeutic drugs and fenretinide varied with the drug used: there was no effect on synergy between fenretinide and cisplatin, but the combination of fenretinide with etoposide became antagonistic. These results suggest that mechanisms mediating synergy between fenretinide and chemotherapeutic drugs lie upstream of GADD153.
authors.affiliation: Northern Institute for Cancer Research, 4th Floor Cookson Building, The Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Corazzari
authors.forename: Penny E
authors.initials: PE
authors.lastname: Lovat
authors.forename: Serafina
authors.initials: S
authors.lastname: Oliverio
authors.forename: Andy D J
authors.initials: AD
authors.lastname: Pearson
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.forename: Christopher P F
authors.initials: CP
authors.lastname: Redfern
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D017313:Fenretinide