Abstract 3323: Induction of apoptosis in glioma cells by downregulation of X-linked inhibitor of apoptosis protein (XIAP)

Abstract

Abstract XIAP (X-linked inhibitor of apoptosis protein) is one of the most important members of the family of apoptosis inhibitors. XIAP blocks apoptosis by inhibiting both the initiator (caspase 9) and effector (caspase 3) caspases, and therefore, prevents cell death induced by various triggers. One mechanism through which tumor cells are believed to acquire resistance to apoptosis is by overexpression of XIAP. When XIAP is overexpressed, cancer cells are rendered resistant to apoptosis, both intrinsically and in response to chemotherapy and radiotherapy. It is upregulated in various malignancies, including human glioblastoma. It promotes invasion, metastasis, growth, and survival of malignant cells. In order to downregulate XIAP in glioma cells, we used human umbilical cord blood mesenchymal stem cells (hUCB) and siRNA of XIAP (siXIAP). We observed the effect of both hUCB and siXIAP on two malignant glioma cell lines (SNB19 and U251) and two glioma xenograft cell lines (4910 and 5310). In either case, proliferation of the glioma cells was significantly inhibited. Both treatments increased cytotoxicity of glioma cells and led to cell death. However, cytotoxicity is more significant in siXIAP treatments compared to hUCB cocultures. Both hUCB and siXIAP induced TNF-alpha-mediated apoptosis in glioma cells, which was confirmed by TUNEL assay, FACS analyses and immunoblotting. Apoptosis is characterized by loss of mitochondrial membrane potential and upregulation of mitochondrial apoptotic protein BAD. Cell death of glioma cells is marked by downregulation of Akt and phospho-Akt molecules. Taken together, our results indicate the therapeutic potential of XIAP and hUCB in treating malignant gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3323.