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|Title:||Role of the survival proteins Hsp27 and survivin in a small molecule sensitization to TRAIL-mediated apoptosis||Authors:||MELLIER GREGORY||Keywords:||cancer, sensitization, TRAIL, Hsp27, survivin, apoptosis||Issue Date:||5-Aug-2010||Citation:||MELLIER GREGORY (2010-08-05). Role of the survival proteins Hsp27 and survivin in a small molecule sensitization to TRAIL-mediated apoptosis. ScholarBank@NUS Repository.||Abstract:||In the last decade, TRAIL has been highlighted as a tumor selective molecule capable of engaging, depending upon the cell type, both the intrinsic and extrinsic apoptotic pathway, making it a promising therapeutic candidate. However, the observation that tumor cells were resistant or could acquire resistance to TRAIL treatment sparked the search for molecules capable of enhancing or restoring sensitivity to TRAIL. One such molecule, LY303511, an inactive analogue of the PI3K inhibitor LY294002, has previously been shown by our group to sensitize different type of tumor cells to TRAIL-induced apoptosis. This sensitization was linked to ROS production, MAPK activation, up-regulation of death receptors expression and clustering, and overall enhancement of DISC formation. Based on the premises that both quercetin and LY29, from which LY30 is derived, could affect the small heat shock protein Hsp27 and the IAP survivin, we set out to investigate the possibility for LY30 to have the same effect. Firstly, the model of LY30 sensitization to TRAIL was assessed in our cell system. We show that pre-incubation of HeLa cells with LY30 significantly amplifies TRAIL signaling as evidenced by decrease cell viability and reduction in the cancer cells colony formation ability. This increase in TRAIL sensitivity involved mitochondrial membrane permeabilization resulting in the release of cytochrome c and Smac/DIABLO, and activation of caspase-3, -8 and -9. Secondly, this study shows that LY30 rapidly induces sustained phosphorylation of Hsp27 dependent on both p38 activity and PP2A inhibition. In addition, Hsp27 phosphorylation is concomitant with a drastic shift in its oligomeric size from large to small oligomers and the dissociation of Hsp27 oligomers is responsible for a marked inhibition of Hsp27 chaperone activity. Furthermore, these effects are combined with a slow and sustain nuclear sequestration. Thirdly, this study demonstrates that LY30 induces the down-regulation of survivin both at the transcriptional and post-translational level. The transcriptional regulation was shown to be due to the induction of Egr-1, a repressor of survivin. Lastly, this study provides evidence of the importance of both survival proteins in the resistance to TRAIL as well as in LY30-mediated sensitization. These findings present a novel mechanism of action of LY30 in sensitization to TRAIL-mediated apoptosis and confirm its potential for the treatment of tumor cells.||URI:||http://scholarbank.nus.edu.sg/handle/10635/23776|
|Appears in Collections:||Ph.D Theses (Open)|
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