Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 24
Apoptotic GSH extrusion as a switch between extrinsic and intrinsic apoptotic pathway:
possible involvement of caspase 2
Milena De Nicola*, Claudia Cerella*, Maria D’Alessio*, Antonio Bergamaschiª, Andrea
Magriniª, Lina Ghibelli*
* Dipartimento di Biologia; ª Cattedra Medicina del Lavoro, Universita' di Roma Tor
Vergata, Via Ricerca Scientifica 1, 00133 Roma, Italia. E.mail:
milena.de.nicola@uniroma2.it
A current paradigm of apoptotic signaling is that different types of apoptogenic stimuli,
physiologic vs damaging, trigger different apoptotic pathways, extrinsic or intrinsic,
respectively. Many recent reports describe cross-talks between these pathways, depending on
cells and/or inducers. Here we describe that damaging agents such as puromycin or etoposide
are able to elicit both apoptotic pathways in a mutually exclusive fashion on human tumor
monocytic U937 cells, and that the switch between the two pathways depends on the
extrusion vs non-extrusion of glutathione. In the first instance, the redox disequilibrium
following GSH loss activates Bax which in turn causes cytochrome c release and caspase 9
activation, i.e., the intrinsic pathway. In the second instance, apoptosis occurs without redox
imbalance and requires caspase 8, in a fashion that is undistinguishable from a canonical
extrinsic pathway triggered by Fas stimulation. Thus, glutathione extrusion is a trigger of the
intrinsic pathway; as such, it is upstream to caspase 9 or 3 activation, but requires caspase 2.
We propose that caspase 2 activates the intrinsic pathway by promoting GSH extrusion; it
may additionally promote caspase 8 activation, possibly explaining why puromycin or
etoposide are able to elicit also the extrinsic pathway.
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