Adenomatous polyposis coli (APC) can recruit protein kinase GSK3 to phosphorylate β-catenin and prevents its downstream transcriptional regulation in nucleus by associated with scaffolding protein Axin. APC mutation contributes to over activating of Wnt signaling by reducing ubiquitin dependent proteasomal degradation of β-catenin. Furthermore, it has been reported that APC mutations play critical role in Taiwanese colorectal cancer (CRC) patients acquiring resistance to clinical 5-fluorouracil (5-FU) treatment by unknown mechanism, which still remains a limitation to CRC treatment outcome. Mutations in kinases including KRAS, BRAF, PIK3CA, PTEN, or TGFβ are most frequently co-occurred with APC mutation in CRC. Recent reports suggested oncogenic roles of β-catanin in drug resistance of Akt inhibitors, and activation of PI3K/Akt signaling confers 5-FU resistance, implying the crosstalk between Wnt and PI3K/Akt pathways in drug resistance. This subproject will investigate how APC and kinases mutations cooperate to drive CRC progression and resistance to therapy. Systems biology provides opportunities to elucidate complex molecular regulations in fundamental biological processes and numerous abnormalities, for instance, drug resistance in cancer progression. The major objective of this proposal is to understand the rewired signaling network of Taiwanese APC mutations for acquired resistance to 5-FU treatment using systems biology analysis. Both global translational level and post-transcriptional modification alterations between wild type and mutated APC genetic backgrounds will be examined and the molecular basis causing drug resistance in Taiwanese CRC will be elucidated. Three Specific Aims will be executed in three years. Aim 1: To investigate the difference between global protein expression profile of CRC baring APC mutation or wild type APC using quantitative proteome analysis. Aim 2: To elucidate the significant signaling alterations in protein phosphorylation of CRC baring APC mutation or wild type APC by phosphoproteome analysis. Aim 3: To construct and validate the rewired regulating networks determining drug resistance in CRC baring APC mutation.
|Effective start/end date||8/1/14 → 7/31/15|