RESUMO
Huntington disease is characterized by neuronal aggregates and inclusions containing polyglutamine-expanded huntingtin protein and peptide fragments (polyQ-Htt). We have used an established cell-based assay employing a PC12 cell line overexpressing truncated exon 1 of Htt with a 103-residue polyQ expansion that yields polyQ-Htt aggregates to investigate the fate of polyQ-Htt-drug complexes. scyllo-Inositol is an endogenous inositol stereoisomer known to inhibit accumulation and toxicity of the amyloid-ß peptide and α-synuclein. In light of these properties, we investigated the effect of scyllo-inositol on polyQ-Htt accumulation. We show that scyllo-inositol lowered the number of visible polyQ-Htt aggregates and robustly decreased polyQ-Htt protein abundance without concomitant cellular toxicity. We found that scyllo-inositol-induced polyQ-Htt reduction was by rescue of degradation pathways mediated by the lysosome and by the proteasome but not autophagosomes. The rescue of degradation pathways was not a direct result of scyllo-inositol on the lysosome or proteasome but due to scyllo-inositol-induced reduction in mutant polyQ-Htt protein levels.
Assuntos
Inositol/farmacologia , Lisossomos/metabolismo , Mutação , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Proteína Huntingtina , Lisossomos/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Células PC12 , Peptídeos/genética , Peptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Ratos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
BACKGROUND: Overexpression of excision repair cross complementing group 1 (ERCC1), a DNA repair enzyme, is associated with resistance to cisplatin. MATERIALS AND METHODS: Tissues from 73 patients with squamous cell carcinoma of the head and neck (HNSCC) who received concurrent cisplatin and radiation was analyzed immunohistochemically to determine if ERCC1 expression predicted for survival and response. Expression was scored as follows: 0=0% tumor nuclei positive, 1+=<50%, 2+=50-75% and 3+=>75%. RESULTS: ERCC1 expression was 0 in 0%, 1+ (14%), 2+ (42%) and 3+ (44%). In uni- and multivariate analyses, 3+ ERCC1 expression was not a significant predictor of survival or response. Median survival for the ERCC1 3+ patients was 2.9 years versus 2.1 years for the ERCC1 <3+ group (p=0.44). CONCLUSION: In this retrospective review of HNSCC patients receiving concurrent cisplatin and radiation, ERCC1 expression was not a significant predictor of survival or response.
