Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Mechanisms that inhibit the propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER 2/neu, activation of Akt, and loss of p53 function. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechan isms activated in response to selection pressures dictates the overall extent of resistance. This experimental result implies the complicated nature of chemoresistance progression, which reflects that several mechanisms con tribute to the multi factorial nature of the chemoresis tance problem.

Although ovarian and lung cancers are assorted malignancies, based on the results of the pathway intersections experiment, several mechanisms are together responsible for platinum based chemoresistance. Table 4 shows the genes that involved in intersected pathways with p value 0. 05 calculated in the expres sion data for ovarian cancer and lung cancer. For exam ple, the expression values for the AKT gene, are not only significantly different in both cancer expression data sets, but the value of betweenness centrality and degree are higher than 3. 8E 4 and 9. 71E 4. In biological terms, the betweenness centrality of a gene measures how many pathways or signal transductions go through that gene. Our experi mental result indicates that the AKT gene plays an important role in chemoresistance associated pathways. Gagnon et al.

suggested that some Akt isoforms, such as Akt2 and Akt3, are involved in chemoresistance to cisplatin and that these isoforms could be putative tar gets for gene therapy for uterine cancers. They per formed biological experiments to demonstrate that Akt activity was directly involved in chemoresistance to cis platin and to find Akt phosphorylation in KLE cells since it was a wild type expressing PTEN cancer cell line. As shown in Table 4, PTEN was the first tumor suppressor gene to be identified in the phosphatase family, and the principal function of its gene product appears to be dephosphorylation of the second messen ger PIP3. The expression of PTEN in two indepen dent glioblastoma cell lines results in the disruption of downstream signaling of PI3K to Akt and Bad.

Thus, when PTEN is present, Akt phosphorylation is blocked and apoptosis mechanisms may be activated. The importance of Akt and AV-951 PTEN genes are as well revealed by this work, which illustrates the accuracy and efficiency of our algorithm. As indicated in Figure 4, the connected gene DVL connects two critical path ways the WNT signaling pathway and the Notch signal ing pathway. Gatcliffe et al. suggested that WNT signaling plays a role in ovarian tumorigenesis.