Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 85
Multiple, independent melatonin-engaged signal transduction pathways are required for
melatonin anti-apoptotic effect.
Flavia Radogna, Laura Paternoster, Silvia Nuccitelli, Maria D’Alessio, Claudia Cerella,
Milena De Nicola, Antonio Bergamaschi*, Lina Ghibelli
Dipartimento di Biologia; *Cattedra Medicina del Lavoro, Università di Roma Tor
Vergata, Via Ricerca Scientifica 1, 00133 Rome Italy. E-mail: flavia.radogna@libero.it
Melatonin, in addition to its main role as regulator of circadian rhythms, has recently been
shown to modulate immune functions by controlling the behaviour of white blood cells
(WBC), which are indeed able to synthesize melatonin and possess the specific high affinity
(1nM) plasma membrane receptors (MT1 and MT2). Great interest is receiving the ability of
melatonin to contrast apoptosis, a well accepted fact whose mechanisms however are still
quite controversial. In this study, we analyze the mechanisms involved in the anti-apoptotic
effect of melatonin in normal and tumor WBC. We have shown that this effect is due to two
different, cooperating mechanisms, involving two primary targets melatonin directly interacts
with, i.e., MT1/MT2 receptors; and calmodulin, a known melatonin low affinity (63uM)
target. Receptor engagement and calmodulin binding give rise to two parallel signal
transduction pathways, consisting of a canonical signal transduction on the one side, and
phospholipase A2 (a known calmodulin interactor) and consequent 5-lipoxygenase (LOX)
activation and 5-HETE production, on the other. The two pathways converge in the inhibition
of Bax dimerisation and activation, key event of the intrinsic apoptotic pathway. The antiapoptotic
effect is completely abrogated if one or the other pathway is inhibited. The
necessity of the low affinity calmodulin binding explains the requirement of high melatonin
doses (>100uM), thus answering to the many perplexities as to whether melatonin antiapoptotic
effect was indeed due to MT1/MT2 receptor stimulation. The involvement of 5-
LOX in the anti-apoptotic effect of melatonin is particularly intriguing since 5-LOX has been
reported to be involved in tumor progression by inhibiting apoptosis in some tumor types. In
addition, the recruitment of a key enzyme of the inflammatory response may shed new lights
on the role melatonin plays in the regulation of the immune response. Moreover, LOX
activation implies a burst of free radicals that immediately (