They systematically exam ined the expressions of apoptosis regulating proteins and PI3K/Akt signaling proteins, finding that OVCAR 3/CDDP cells were 4. 8 fold more resistant to cisplatin than OVCAR 3 cells following 72 h exposure to the drug. This resistance correlated with reduced suscept ibility to cisplatin induced apoptosis. Apoptotic proteins were differentially expressed in the OVCAR 3/CDDP cells, resulting in the inhibition of Bax translocalization. Their experimental results indicate that the development of resistance in OVCAR 3 cells is derived from increas ing PIK3CA transcription and reducing of PTEN expres sion. These alterations confer resistance to cisplatin through the activation of PI3K. These in vivo results support the proposition that our algorithm can identify chemoresistance associated pathways.

In Figure 3, genes are represented by red squares indi cating the connected nodes. that is, these genes connect two pathways. Connected nodes are key factors for join ing two or more metabolic pathways or passing down signals. Taking GRB2 as an example, LEsperance et al. found that upregulated genes in post chemotherapy ovarian tumors included a substantial number of genes with previously implicated in mechanisms of chemoresistance including COX2 and tumorigenesis, GRB2. As seen in Figure 3, AKT was also identified as a connected gene, and had significant betweenness centrality and degree values, indicating that AKT has potential to act as a hub node in biological interaction networks and be involved in chemoresistant mechan isms as well.

Significant results following pathway intersections GSK-3 The main analysis of this experiment focused on whether different cancers identical chemoresistant mechanisms and whether these chemoresistant mechan isms share some genes in common. After performing intersection by Formula, 88 pathways remained. The following sections include further analysis. The major goals of this analysis were to explore pathways or genes involved in chemoresistant mechan isms. to delineate how these genes or pathways interact with each other. to test whether the p values of the genes in this pathway are significantly differen tially expressed. to analyze the betweenness central ity and degree values of genes in this pathway. and to identify the chemoresistance associated genes.

As shown in the Diagram 4, several pathways contrib uted to this result the colorectal cancer related pathway, the hedgehog signaling pathway, the WNT signaling pathway and the notch signaling pathway. In addition, some other pathways, such as the p53 signaling pathway, the MAPK signaling pathway, and the focal adhesion were partially involved as well. Platinum based cancer drugs are among the most potent anti tumor agents, displaying clinical activity against a wide variety of solid tumors.