Phosphatidylinositol 3-kinase inhibitor(LY294002) induces apoptosis of human nasopharyngeal carcinoma in vitro and in vivo

The activation of the PI3K/Akt and its effect on CNE-2Z cells in vivo and in vitro was investigated by MTT assay, flow cytometry, western blot, ELISA, terminal deoxyribonucleotide transferase-mediated nick-end labeling assays (TUNEL), and immunohistochemical analyses, using PI3K inhibitor, LY294002.The results showed that LY294002 inhibited the phosphorylating of Akt (S473), cell proliferation, and induced apoptosis in CNE-2Z cells. However, our experiment results also demonstrated that apoptosis-induced LY294002 was directly regulated by caspase-9 activation pathway.These data suggested that PI3K inhibitor, LY294002, induced apoptosis by caspase-9 activation pathway and might be as a potentially useful target for therapeutic intervention in nasopharyngeal carcinoma patients.Nasopharyngeal carcinoma (NPC) has a distinct epidemiology and distribution, southern China and Southeast Asia are the highest risk areas, while rare in most parts of the world. Although many NPC patients may undergo radiation therapy for possibly cure and new strategies have improved survival for patients with metastasis, 30%-40% NPC patients die from local recurrence and metastasis. A better understanding of signaling pathways contributing to NPC survival and apoptosis will provide targets for new therapeutic agents.The phosphatidylinositol-3 OH kinase (PI3K)/Akt signaling pathway has been shown to contribute to cancer survival, apoptosis, and regulating a variety of cellular processes. In particular, Akt serine/threonine kinase is believed to play a critical role in controlling the balance between cell survival and apoptosis [1]. Previous studies had shown that phosphatidylinositol 3,4,5-trisphosphate(PIP3) generated by PI3K acts as a lipid second messenger essential for the translocation of protein kinase B(Akt) to the plasma membrane [2,3]. Akt is phosphorylated at two sites, T308 in kinase domain and S473 in regulatory tail. Phosphorylation at T308 and S473 is essential for maximal Akt act