engleski

Expression of galectin-3, an anti-apoptotic molecule is not affected in apoptosis provoked with 17-DMAG, an inhibitor of Hsp90

Heat shock protein of Mr 90 kDa (Hsp90) comprises 2 homologous (Hsp90α and Hsp90β) stress-inducible molecular chaperons that are encoded by separate genes. These highly conserved, homo-dimeric ATP-dependent proteins, abundantly expressed in eukaryotic cells, account for the maturation and functional stability of a plethora of polypeptides termed Hsp90 client proteins, including many proteins involved in tumorigenesis (e.g. anti-apoptotic proteins, transcription factors, signal- transduction proteins, Tyr-kinase receptors, etc.). Inhibition of HSP90 has been shown to be a promising therapeutic approach with clinical relevance for treatment of specific tumour types. Orally bio-available derivative of ansamycin antibiotic geldanamycin, 17-DMAG [17- (dimethylaminoethyl¬amino)-17- demethoxygeldanamycin] through inhibition of Hsp90 causes down-regulation of Hsp90 client proteinswhich lead to impaired signalling of apoptosis. Galectin-3, a β-galactosidelectinis a multifunctional protein that is ubiquitously expressed in both intracellular and extracellular environments as well as on the surface of different types of cells of many tissues. Intracellular galectin-3 was shown to be a strong anti-apoptotic molecule, and it is well known for its roles being correlated with the development and malignancy of cancers and cancer drugresistance. It this study we explored the effects of 17- DMAG on the expression of galectin-3, different heat shock protein family members (Hsp90α, Hsp90β, Hsp70, Hsp27) and Hsp90 client proteins involved in cell cycle regulation (cdk1, p(Tyr)-cdk1 and cdc2) in human acute monocyticleukaemia THP-1 cells. Cell we treated with 0.5, 2, or 3 μM 17- DMAG for 24, 48 and 72 hours. Cytotoxic and pro-apoptotic effects of 17-DMAG estimated by ApoToxGlo assay, were time and concentration dependent. 17-DMAG slightly induced the expression of both Hsp90α and Hsp90β, tremendously up-regulated the expression of HSP70, but did not affect the expression of Hsp27. In parallel, 17-DMAG did not affect expression of intracellular expression of galectin-3, an anti-apoptotic molecule important for cell survival. It seems that molecular pathways resulting in apoptosis provoked by inhibition of Hsp90 with 17-DMAG bypass galectin-3. These results encourage for further studies focused on elucidation of galectin-3 role in apoptosis, but also the effects of 17-DMAG on molecular level.

galectin-3 ; apoptosis ; Hsp90

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