OP199: Gelsolin regulates chemoresistance of human head and neck cancers

Purpose Chemoresistance is a major challenge in cancer therapy. Recent research indicates that down-regulation of the apoptosis pathways is one of the key determinants for chemoresistance. Gelsolin (GSN) has been discovered to participate the common effector of apoptosis. This study aimed to explore the role and mechanism of gelsolin in head and neck chemoresistance. Material and methods Gelsolin expression were evaluated in 22 recurrent oral cancer patients accept cisplatin (CDDP) treatment. Western blot and RT-QPCR were applied to check gelsolin expression in paired head and neck cancer lines with different levels of chemoresistance. Modulation of intracellular full length and truncated gelsolin levels were performed in cancer cells to reveal its molecular mechanisms. We then use yeast-two-hybrid screening and bioinformatics to identify candidate players in the gelsolin signaling network involved chemoresistance. Confocal microscopy was used to observe subcellular localization of gelsolin and its binding proteins. Results We observed higher level of GSN in chemoresistant oral cancers than the sensitive counterparts, consistent with clinical observation in 22 stage IV oral cancer patients subject to standard CDDP regimen. CDDP-induced GSN down-regulation is associated with its cleavage and apoptosis. While C-terminus GSN fragment sensitizes chemoresistant cells to CDDP-induced apoptosis, intact GSN and its N-terminal fragment attenuated this response. Silencing GSN facilitated CDDP-induced apoptosis in chemoresistant cells. In contrast, intact GSN is pro-survival in the presence of CDDP through interaction with FLIP and Itch. This interaction is co-localized in the perinuclear region that could be dissociated by CDDP in sensitive cells, thereby inducing FLIP ubiquitination and degradation followed by apoptosis. In resistant cells, GSN is highly expressed and CDDP fails to abolish the I-GSN-FLIP-Itch interaction, resulting in the dysregulation of the downstream responses. Conclusions This study revealed that I-GSN is an important player in cancer chemoresistance and may serve as a molecular target for chemoresistance.