Through systematic profiling expression of apoptosis pathway proteins with respect to histological sub-types of non-small cell lung cancer in human lung cancer cell lines, we have identified specific patterns of defects in the expression and regulation of apoptosis pathways in lung cancer cells. Also, these apoptosis pathway differences between lung cancer cell types may correlate with specific intra-cellular road-blocks that are critical to overcome in order to cause cell death in the lung cancer cell. Previously, we have performed studies which show that knock-down of specific anti-apoptosis molecules can successfully render an apoptosis-resistant lung cancer cell more susceptible to apoptosis induction, resulting in cancer cell death. Our goal to elucidate the mechanisms responsible for the differences in apoptosis expression in lung cancer sub-types has led us to identify a specific microRNA which is involved in the regulation of the translational expression of the most potent IAP (inhibitor of apoptosis). Furthermore, we have characterized the binding site on the messenger RNA critical for the microRNA-messenger RNA interaction. The actions of this particular microRNA can down-regulate the expression of IAP, therefore rendering the cancer cell more susceptible to cell-death induction by other pro-apoptosis agents. In pursuing this work, we identified a cytogenetic abnormality which is responsible for the decreased expression of the microRNA in particular lung cancer cells. We are currently exploring other mechanisms whereby microRNA expression may be altered in the lung cancer cells. From this related work, we have identified another microRNA which significantly inhibits cancer cell proliferation. How this specific microRNA can exert its effects against the cancer cell is the work currently underway in the lab. The knowledge gained from this project is directly integrated into the novel therapeutics project in the laboratory.
|Xie, Y; Tobin, L A; Camps, J et al. (2013) MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells. Oncogene 32:2442-51|