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Laboratory of Cell and Developmental Genetics, Department of Medicine, Université Laval and CHUL Research Center, Ste-Foy, Quebec, Canada G1K 7P4
1Correspondence: Laboratory of Cell and Developmental Genetics, Department of Medicine, Pav. CE. Marchand, Université Laval, Ste-Foy, Qc, Canada, G1K 7P4. E-mail: Robert.Tanguay{at}rsvs.ulaval.ca
Hereditary tyrosinemia type I is the most severe metabolic disease of
the tyrosine catabolic pathway mainly affecting the liver. It is caused
by deficiency of fumarylacetoacetate hydrolase, which prevents
degradation of the toxic metabolite fumarylacetoacetate (FAA). We
report here that FAA induces common effects (i.e., cell cycle arrest
and apoptosis) in both human (HepG2) and rodent (Chinese hamster V79)
cells, effects that seem to be temporally related. Both the
antiproliferative and apoptosis-inducing activities of FAA are dose
dependent and enhanced by glutathione (GSH) depletion with
L-buthionine-(S,R)-sulfoximine (BSO). Short treatment (2 h) with 35
µM FAA/+BSO or 100 µM FAA/-BSO induced a transient cell cycle
arrest at the G2/M transition (20% and 37%, respectively) 24 h
post-treatment. In cells treated with 100 µM FAA/-BSO, an
inactivation, followed by a rapid over-induction of cyclin B-dependent
kinase occurred, which peaked 24 h post-treatment. Maximum levels
of caspase-1 and caspase-3 activation were detected at 3 h and
32 h, respectively, whereas release of mitochondrial cytochrome
c was maximal at 24–32 h post-treatment. The G2/M peak
declined 24 h later, concomitantly with the appearance of a
sub-G1, apoptotic population showing typical nucleosomal-sized DNA
fragmentation and reduced mitochondrial transmembrane potential
(
m). These events were prevented by the general
caspase inhibitor z-VAD-fmk, whereas G2/M arrest and subsequent
apoptosis were abolished by GSH-monoethylester or
N-acetylcysteine. Other tyrosine metabolites,
maleylacetoacetate and succinylacetone, had no antiproliferative
effects and induced only very low levels of apoptosis. These results
suggest a modulator role of GSH in FAA-induced cell cycle disturbance
and apoptosis where activation of cyclin B-dependent kinase and
caspase-1 are early events preceding mitochondrial cytochrome
c release, caspase-3 activation, and m
loss.—Jorquera, R., Tanguay, R. M. Cyclin B-dependent kinase and
caspase-1 activation precedes mitochondrial dysfunction in
fumarylacetoacetate-induced apoptosis.
Key Words: cell cycle • caspase • cytochrome c • glutathione • cell death
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