Survivin Splice Variants in Arsenic Trioxide (As₂O₃)-Induced Deactivation of PI3K and MAPK Cell Signalling Pathways in MCF-7 Cells.

Several pathways are deregulated during carcinogenesis but most notably, tumour cells can lose cell cycle control and acquire resistance to apoptosis by expressing a number of anti-apoptotic proteins such as the Inhibitors of Apoptosis Protein (IAP) family of proteins that include survivin, which is implicated in cancer development. There is no study which had proven that arsenic trioxide (As₂O₃) has any effect on the splicing machinery of survivin and its splice variants, hence this study was aimed at determining the cytotoxic effect of As₂O₃ and its effect on the expression pattern of survivin splice variants in MCF-7 cells. As₂O₃ inhibited the growth of the MCF-7 cells in a concentration-dependent manner. The Muse Cell Analyser showed that As₂O₃-induced G2/M cell cycle arrest, promoted caspase-dependent apoptosis without causing any damage to the mitochondrial membrane of MCF-7 cells. As₂O₃ also deactivated two survival pathways, Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K) signalling pathways in MCF-7 cells. Deactivation of the two pathways was accompanied by the upregulation of survivin 3α during As₂O₃-induced G2/M cell cycle arrest and apoptosis. Survivin 2B was found to be upregulated only during As₂O₃-induced G2/M cell cycle arrest but downregulated during As₂O₃-induced apoptosis. Survivin wild-type was highly expressed in the untreated MCF-7 cells, the expression was upregulated during As₂O₃-induced G2/M cell cycle arrest and it was downregulated during As₂O₃-induced apoptosis. Survivin variant ΔEx3 was undetected in both untreated and treated MCF-7 cells. Survivin proteins were localised in both the nucleus and cytoplasm in MCF-7 cells and highly upregulated during the As₂O₃-induced G2/M cell cycle arrest, which can be attributed to the upregulation of survivin-2B. This study has provided the first evidence showing that the novel survivin 2B splice variant may be involved in the regulation of As₂O₃-induced G2/M cell cycle arrest only. This splice variant can therefore, be targeted for therapeutic purposes against Luminal A breast cancer cells.