IQUIFIB   02644
INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
artículos
Título:
Endosomes and lysosomes are involved in early steps of Tl(III)-mediated apoptosis in rat pheochromocytoma (PC12) cells
Autor/es:
HANZEL, CE; ALMEIRA GUBIANI, MF; VERSTRAETEN, SV
Revista:
ARCHIVES OF TOXICOLOGY.
Editorial:
SPRINGER
Referencias:
Año: 2012
ISSN:
0340-5761
Resumen:
The
mechanisms that mediate thallium (Tl) toxicity are still not completely
understood. The exposure of rat pheochromocytoma (PC12) cells to Tl(I) or
Tl(III) activates both mitochondrial (Tl(I) and Tl(III)), and extrinsic (Tl(III))
pathways of apoptosis. In this work we evaluated the hypothesis that the
effects of Tl(III) may be mediated by the damage to lysosomes, where it might
be incorporated following the route of iron uptake. PC12 cells exposed for 3 h
to 100 uM Tl(III) presented marked endosomal
acidification, effect that was absent when cells were incubated in a serum-free
medium, and that was fully recovered when the latter was supplemented with transferrin. After 6 h of incubation the co-localization of cathepsins D and
B with the lysosomal marker Lamp-1 was decreased together with an increase in
the total activity of the enzymes. A permanent damage to lysosomes after
18 h of exposure was evidenced from the impairment of acridine orange uptake. Cathepsins
D caused the cleavage of pro-apoptotic protein BID that is involved in the
activation of the intrinsic pathway of apoptosis. Supporting that, BID cleavage
and the activation of caspase 3 by Tl(III) were fully prevented when cells were
preincubated with cathepsin D inhibitor (pepstatin A) and only partially
prevented when cathepsin B inhibitor (E64d) was used. None of these inhibitors
affected BID cleavage or caspase 3 activation in Tl(I)-treated cells. Together,
experimental results support the role of Tl(III) uptake bye the acidic cell
compartments and their involvement in the early steps of Tl(III)-mediated PC12
cells apoptosis.