Targeted inhibition of heat shock protein 90 disrupts multiple oncogenic signaling pathways, thus inducing cell cycle arrest and programmed cell death in human urinary bladder cancer cell lines.
Cancer Cell Int
; 13(1): 11, 2013 Feb 08.
Article
em En
| MEDLINE
| ID: mdl-23394616
ABSTRACT
BACKGROUND:
Geldanamycin (GA) can be considered a relatively new component with a promising mode of action against human malignancies. It specifically targets heat shock protein 90 (Hsp90) and interferes with its function as a molecular chaperone.METHODS:
In this study, we have investigated the effects of geldanamycin on the regulation of Hsp90-dependent oncogenic signaling pathways directly implicated in cell cycle progression, survival and motility of human urinary bladder cancer cells. In order to assess the biological outcome of Hsp90 inhibition on RT4 (grade I) and T24 (grade III) human urinary bladder cancer cell lines, we applied MTT assay, FACS analysis, Western blotting, semi-quantitative (sq) RT-PCR, electrophoretic mobility shift assay (EMSA), immunofluorescence and scratch-wound assay.RESULTS:
We have herein demonstrated that, upon geldanamycin treatment, bladder cancer cells are prominently arrested in the G1 phase of cell cycle and eventually undergo programmed cell death via combined activation of apoptosis and autophagy. Furthermore, geldanamycin administration proved to induce prominent downregulation of several Hsp90 protein clients and downstream effectors, such as membrane receptors (IGF-IR and c-Met), protein kinases (Akt, IKKα, IKKß and Erk1/2) and transcription factors (FOXOs and NF-κΒ), therefore resulting in the impairment of proliferative -oncogenic- signaling and reduction of cell motility.CONCLUSIONS:
In toto, we have evinced the dose-dependent and cell line-specific actions of geldanamycin on cell cycle progression, survival and motility of human bladder cancer cells, due to downregulation of critical Hsp90 clients and subsequent disruption of signaling -oncogenic- integrity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Cancer Cell Int
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Grécia