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Session 7: Cancer signaling networks Poster 4
The inhibition of poly(ADP-ribosylation) affects cancer cell proliferation and telomere
elongation
Cristina Belgiovine, Francesca Donà, Ilaria Chiodi, Tatiana Raineri, Roberta Ricotti,
Chiara Mondello and A. Ivana Scovassi
Istituto di Genetica Molecolare CNR, Via Abbiategrasso 207, I-27100 Pavia, Italy
belgiovine@igm.cnr.it
Poly(ADP-ribosylation) plays a central role in Base Excision Repair (BER) and also in
neoplastic transformation and telomere length regulation. It is catalyzed by a family of
poly(ADP-ribose) polymerases (PARPs), of which the best characterized are PARP-1, PARP-
2, TANK-1 and TANK-2, which convert NAD into ADP-ribose further used to form
polymers. We investigated their expression levels during neoplastic transformation of cen3tel
cells, which derive from human fibroblasts immortalized by ectopic hTERT expression and,
during propagation in vitro, acquired the ability to grow in agar and subsequently to form
tumors in nude mice. Upon further propagation, tumorigenic cells became more aggressive,
showing a reduction in the time required to induce tumors; moreover, they reached telomere
lengths >100 Kb and increased telomerase activity. We found a notable increase of PARP-1
protein (and mRNA) in parallel to the acquisition of the tumorigenic potential; PARP-2 levels
showed the same trend, while tankyrase expression did not show significant changes. As
supported by poly(ADP-ribose) accumulation, overexpressed PARP-1 and -2 were very
active, thus suggesting that poly(ADP-ribosylation) is modulated during neoplastic
transformation and could be a target for contrasting tumor development. To address this point,
we analyzed the effect of the known PARP inhibitor, 3-aminobenzamide (3-AB), on cell
proliferation and telomere length. Increasing concentrations of 3-AB inhibited the
proliferation of neoplastic cells in a dose-dependent manner. Remarkably, prolonged 3-AB
administration to early tumorigenic cells also affected telomere length. On the whole, our data
support an active involvement of poly(ADP-ribosylation) in neoplastic transformation and
telomere length maintenance. Thus, our work provides additional evidence in favor of the use
of PARP inhibitors for the treatment of human cancer [Donà et al., Curr. Pharmaceut.
Biotechnol. (2010), in press].
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