Abstract 238: Role of GSK3β in modulating TRAIL-induced apoptosis in prostate cancer cells
Authors: Nithyananda Thorenoor, Ramesh Thylur, Ajay Rana, Basabi Rana
Journal: Cancer Research (2012)

Abstract Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death in males. Surgical excision and hormonal therapy are the first-line of treatments, which are not effective at later-stages. Designing efficient non-invasive therapeutic strategies that can target prostate cancer cells towards apoptosis is critically important, thus making the apoptotic signaling pathways as attractive targets for cancer therapy. The ability of cancer cells to evade apoptosis is a hallmark of oncogenesis, and a major setback in current therapy. TNF-related apoptosis inducing ligand (TRAIL) has gained much importance recently due to its ability to preferentially induce cell death in malignant and transformed cells but not in normal cells. However, since many tumor cells develop resistance to TRAIL, recent approaches are focused on developing combinatorial therapeutic regimens that can enhance TRAIL sensitivity. There are multiple reasons behind TRAIL resistance, and recent studies (including ours) indicate that, Glycogen Synthase Kinase 3β (GSK3β) might be a key player in mediating this. GSK3β, a multifunctional serine/threonine kinase regulates diverse physiological processes, depending on its substrates, and its kinase activity seems to be critical for various cancer cells. In our earlier studies, combinatorial treatment with Troglitazone (TZD), a synthetic ligand for peroxisome proliferator-activator receptor gamma and TRAIL induced significant apoptosis in TRAIL-resistant cancer cells. More in-depth analysis of the signaling pathways promoting TRAIL resistance indicated that pretreatment of resistant prostate cancer cells with a pharmacological inhibitor of GSK3β (AR-A014418) ameliorates TRAIL resistance and synergizes with TZD to induce potent apoptosis. In addition, small interference RNA (siRNA)-mediated knockdown of GSK3β expression promoted TRAIL-TZD-induced apoptosis, whereas ectopic expression of GSK3β antagonized this. Further studies indicated a TRAIL-TZD-induced decrease in total GSK3β expression and increase in GSK3βSer9 phosphorylation (inactivation) in apoptotic cells. Pre-treatment with caspase inhibitors protected the cells from apoptosis, but was unable to reverse the effects of TRAIL-TZD on GSK3β, suggesting these to be caspase independent. Pretreatment with protein synthesis inhibitor Cycloheximide abolished the inhibitory effects of TRAIL-TZD on total GSK3β, suggesting this to be a transcriptional event. In fact, luciferase assays indicated a significant reduction of GSK3β promoter activity following this combination treatment. The results from the present study show that, targeting GSK3β might be an effective mechanism of increasing TRAIL sensitivity, and understanding the detailed mechanism by which TRAIL-TZD combination antagonizes GSK3β pathway might provide novel insight to improve our understanding of TRAIL resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 238. doi:1538-7445.AM2012-238