Impact of MDM2 on the Expression Level of XIAP on Various Cancer Cell Lines

Impact of MDM2 on the Expression Level of XIAP on Various Cancer Cell Lines

Transcription of the mouse double minute 2 homolog (MDM2) gene is amplified during cancer development and continues through disease progression. X-linked inhibitor of apoptosis protein (XIAP)- MDM2 heterodimerization occurs when XIAP binds to the RING domain of the MDM2. This interaction is a pro-cancerous mechanism, which counteracts the cellular stress caused by cancer therapy, and plays a significant role in the stabilization of MDM2 and related functions. Additionally, XIAP inhibits the pro-apoptotic proteins caspase 3, 7 and 9; which are key factors in intrinsic cellular apoptosis. The objective of the study is to test the effect of MDM2 inhibitor RG7388 to determine whether inhibition of MDM2 decrease the level of XIAP in MDM2 overexpressing cancer cell lines. Initially, the expression level of XIAP was tested in the following cell lines: LNCaP (Prostate), LNCaP- MST (MDM2 transfected LNCaP cells), SJSA-1 (Osteosarcoma) and GI-101A (breast). Notably, the XIAP expression is significantly higher inthe LNCaP-MST and SJSA-1 cell lines, which has elevated expression of MDM2. So far our results show a positive correlation between MDM2 and XIAP expression. Treatment with RG7388 showed a decrease in the levels of XIAP, which is well correlated with the upregulated levels of caspase enzymes, and activation of intrinsic apoptosis pathway. However, further studies are warranted to confirm the intracellular mechanisms involved in the regulation of XIAP in MDM2 positive cancers. (This project was supported by The Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida).