Abstract A26: Autophagy acts as a safeguard mechanism against G-quadruplex ligand-mediated telomere damage.

G-quadruplex structures have attracted considerable interest as targets for the development of novel anticancer therapies due to their capability to interfere with telomere structure and function. Elucidation of the structures of telomeric G-quadruplexes has led, in the past few years, to the rational development of effective G-quadruplex-stabilizing small molecules. In the present study we show that short-term exposure of melanoma cells to Ant1,5 (an anthracene-based telomeric G-quadruplex stabilizer) impaired cell growth without inducing cell senescence or apoptosis. Conversely, drug-treated cells were characterized by the occurrence of typical biochemical and morphological features usually associated to autophagy, such as an increase in the lipidated form of the autophagic marker LC3b and its co-localization with the lysosome marker LAMP2A. Such drug-induced autophagy occurred as a consequence of telomere uncapping and associated DNA damage response, through a pathway converging on the cyclin-dependent kinase inhibitor p21 waf1 . The inhibition of autophagy by the pharmacologic inhibitor Bafilomycin A1 or through RNAi-mediated depletion of ATG5 gene enhanced the cytotoxic activity of Ant1,5, as revealed by the marked increase in drug-induced apoptosis. Our data outline a molecular scenario in which G-quadruplex ligand-induced telomeric dysfunctions are translated into an autophagic response and provide the first evidence of autophagy as a safeguard mechanism activated by melanoma cells to counteract drug-mediated telomeric stress. As a consequence, interference with the autophagy pathway in melanoma could be a suitable approach to extend the therapeutic options for this malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A26.