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FBXW7 mutations occur in a variety of human cancers including colorectal cancer (CRC). Elucidating its mechanism of action has become crucial for cancer therapy; however, it is also complicated by the fact that FBXW7 can influence many pathways due to its role as an E3-ubiquitin ligase in proteasome degradation. FBXW7 and TP53 are tumour suppressors intensively implicated in colorectal carcinogenesis. Deletion mutations in these two genes in animal models mark the progression from adenoma to carcinoma. Although still largely unknown, the last defense mechanism against CRC at the molecular level could be through a synergistic effect of the two genes. The underlying mechanism requires further investigation. In our laboratory, we have used a phospho-kinase profiler array to illustrate a potential molecular link between FBXW7 and p53 in CRC cells. In vitro and in vivo assessments demonstrated aberrant induction of phosphorylated p53 at Serine 15 [phospho-p53(Ser15)] in human FBXW7-deficient CRC cells as compared to their FBXW7-wild-type counterparts. FBXW7 loss in HCT116 cells promoted resistance to oxaliplatin. Immunoblotting data further confirmed that reduction of phospho-p53(Ser15) may contribute to the decreased efficacy of therapy in FBXW7-mutated CRC cells. The findings may suggest the applicability of phospho-p53(Ser15) as an indicative marker of FBXW7-mutations. Phospho-p53(Ser15) regulation by FBXW7 E3-ligase activity could provide important clues for understanding FBXW7 behavior in tumour progression and grounds for its clinical applicability thereafter.

Original publication

DOI

10.18632/oncotarget.3284

Type

Journal article

Journal

Oncotarget

Publication Date

20/04/2015

Volume

6

Pages

9240 - 9256

Keywords

CK1α, FBXW7, colorectal cancer, drug resistance, phopsho-P53(Ser15), Antineoplastic Agents, Biomarkers, Tumor, Cell Cycle Proteins, Cell Line, Tumor, Colorectal Neoplasms, Drug Resistance, Neoplasm, F-Box Proteins, F-Box-WD Repeat-Containing Protein 7, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Organoplatinum Compounds, Phosphorylation, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases